1-(Arylmethyl)quinazoline-2,4(1H,3H)-diones as PARP Inhibitors and the Use Thereof

ABSTRACT

Disclosed are 1-(arylmethyl)quinazoline-2,4(1H,3H)-diones thereof, represented by the Formula (I) wherein Ar, R 1 -R 6  are defined herein. Compounds having Formula (I) are PARP inhibitors. Therefore, compounds of the invention may be used to treat clinical conditions that are responsive to the inhibition of PARP activity.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is in the field of medicinal chemistry. In particular,the invention relates to 1-(arylmethyl)quinazoline-2,4(1H,3H)-diones,and the use of these compounds as PARP inhibitors and anti-cancer drugs.

2. Related Art

Poly (ADP-ribose) polymerase (PARP) catalyzes the addition of poly(ADP-ribose) to the target protein using NAD+ that is an importantprocess in DNA repair. This is an essential process for maintaining DNAand chromosome integrity and stability, and for ensuring the survival ofmammalian cells. PARP-1 catalyzes the majority of the intracellularADP-ribose polymerization reactions, although PARP-2 and other subtypesalso have this function. The PARP-1 knockout mice do not have the repairfunction for single-stranded DNA damages (Krishnakumar and Kraus, 2010,Molecular Cell 39:8). Cancer cells with DNA repair defects, such asBRCA1 (breast cancer 1) or BRCA2 (breast cancer 2) deficiency, areparticularly sensitive to DNA damaging anticancer agents, includingplatinum chemotherapy drugs, DNA methylation anticancer drugs and DNAtopoisomerase inhibitors, or radiation therapy. Phase II clinical trialdata have shown that PARP-1 inhibitor olaparib (AZD2281) was effectivefor the treatment of advanced breast cancer (Andrew Tutt et al., 2009,J. Clin. Oncol 27:18 s; Andrew Tutt et al., 2010 Lancet 376:235; RA Dentet al., 2010 J. Clin. Oncol. 28:15 s). These scientific and clinicalresults demonstrated that PARP-1 inhibitors may be used as effectiveanti-cancer drugs to treat a variety of cancers. The applications ofPARP-1 inhibitors for the treatment of cancer are mainly based on twomechanisms. First, because of the rapid growth, DNA replication is muchhigher in cancer cells than in normal cells. Drugs that cause DNA damagewill induce cancer cell death selectively. However, due to the presenceof DNA repair enzymes such as PARP-1, the therapeutic effects of thesedrugs can not be fully materialized. By inhibiting the DNA repairmechanism, PARP-1 inhibitors in combination with commonly used DNAdamaging anti-cancer drugs, such as temozolomide, can achieve synergyeffects and greatly enhance the anticancer effects of currently usedanticancer drugs. Second, for cancer cells with DNA repair deficiency,such as BRCA1 or BRCA2 deficient triple-negative breast cancer, PARP-1inhibitors can directly kill the cancer cells and function as anticancerdrugs independently. According to statistics, about 10-15% of breastcancer patients have family history of genetic factors, in which theBRCA1 or BRCA2 gene mutations account for 15-20% of all hereditarybreast cancers. Since PARP-1 is involved in DNA repair, utilization ofPARP-1 inhibitors to inhibit DNA repair may be an effective andselective treatment for cancers with DNA repair genetic defect,including triple-negative breast cancers. Furthermore, PARP-1 inhibitorsmay also be used to treat diseases due to excessive cell death,including central nervous system diseases such as stroke andneurodegenerative diseases (Akinori Iwashita et al., 2004, J. Pharmacol.Exp. Thera. 310: 425).

The inhibitory activity of PARP-1 inhibitors can be measured by directlyusing PARP-1 enzymes. In addition, since PARP-1 inhibitors can increasethe cytotoxicity of DNA damaging anti-cancer drugs such as methylmathanesulfonate (MMS) on cancer cells, the activity of PARP-1inhibitors can also be determined by measuring cell viability, such asusing a MTT assay, in the presence of MMS and PARP-1 inhibitors.Furthermore, Cancer cells with deficiency in DNA repair, such as in thecase of BRCA1 or BRCA2 deficient triple-negative breast cancer, can bekilled by PARP-1 inhibitors alone. Therefore the anticancer activity ofPARP-1 inhibitors can be determined by measuring the inhibitory effectof these compounds on cell growth of BRCA-2 deficient CAPAN-1 humanpancreatic cancer cells.

It has been known that many cancer chemotherapeutic drugs trigger cancercells to undergo apoptosis. The mechanism of apoptosis involves acascade of initiator and effector caspases that are activatedsequentially. Caspases are a family of cysteine proteases that requireaspartic acid residues at the P₁ position of substrates for efficientcleavage. Among these caspases, caspase-3, 6, and 7 are key effectorcaspases that cleave multiple protein substrates in cells, leading tocell death. Cellular caspase activity can be determined using caspasesubstrates and used as a measurement of cell apoptosis. PARP-1inhibitors can increase the apoptosis-inducing activity of many DNAdamaging anticancer drugs such as MMS. Therefore, the activity of PARP-1inhibitors can be determined via measuring the intracelluar caspaseactivity of cancer cells treated with DNA damaging anticancer drugs incombination with PARP-1 inhibitors.

JP2007137818 disclosed the preparation of8-hydroxyquinazoline-2,4(1H,3H)-dione derivatives as poly(ADP-ribose)polymerase (PARP) inhibitors, wherein X═(CH₂)_(n); n=an integer of 1-4;Y═H, NR₁R₂, 1,2,3,4-tetrahydroisoquinolyl, decahydroisoquinolyl,1,3-dioxo-1,3-dihydro-2H-isoindolyl, 3-oxo-3,4-dihydrobenz[1,4]oxazinyl,pyridyl, benzyl, (un)substituted optionally fused 5-memberedN-heterocyclyl, and (un)substituted aryloxy, etc.

WO2006003148 disclosed the preparation of quinazolinedione derivativesas PARP inhibitors for the treatment of PARP mediated diseases, whereinX and Y are each independently N or CH; L₁=a bond or alkylene; L₂=abond, CO, alkylene, CO-alkylene, etc.; R₁═H or OH; Z═H or(un)substituted (hetero)aryl; etc.

SUMMARY OF THE INVENTION

The invention provides novel1-(arylmethyl)quinazoline-2,4(1H,3H)-diones, as represented in FormulaeI, II and III. These compounds have PARP inhibitory activities.

The present invention also provides pharmaceutical compositionscomprising a compound of Formula I, II or III in an effective amount forthe treatment of cancer.

The invention also provides a pharmaceutical composition useful for thetreatment of cancer, containing an effective amount of a compound of oneof the Formula I, II or III in admixture with one or morepharmaceutically acceptable carriers or diluents.

The invention also provides a pharmaceutical composition useful for thetreatment of cancer, containing an effective amount of a compound of oneof the Formula I, II or III, in combination with one known anticancerdrugs or its pharmaceutically acceptable salts.

The invention also is directed to methods for the preparation of novelcompounds of Formulae I, II and III.

DETAILED DESCRIPTION OF THE INVENTION

The novel and potent PARP inhibitors of the present invention include1-(arylmethyl)quinazoline-2,4(1H,3H)-diones, as represented in FormulaeI, II and III.

Specifically, compounds of the present invention are represented byFormula I:

or pharmaceutically acceptable salts or prodrugs thereof, wherein:

Ar is an optionally substituted aryl or an optionally substitutedheteroaryl;

R₁-R₆ independently are hydrogen, halo, optionally substituted amino,optionally substituted alkoxy, optionally substituted C₁₋₁₀ alkyl,haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, carboxyalkyl,nitro, cyano, acylamido, hydroxy, thiol, acyloxy, azido, carboxy,ethylenedioxo, carbonylamido or optionally substituted alkylthiol.

Preferred compounds of Formula I include compounds wherein Ar is anoptionally substituted phenyl, pyridyl or furanyl. More preferably, Aris phenyl, pyridyl or furanyl, optionally substituted with a substitutedcarbonyl or methyl, preferably carbonyl, at the meta-position. Anothergroup of preferred compounds of Formula I include compounds wherein R₅and R₆ are hydrogen.

One group of preferred compounds of the present invention arerepresented by Formula II:

or pharmaceutically acceptable salts or prodrugs thereof, wherein:

R₁-R₄ independently are hydrogen, halo, optionally substituted amino,optionally substituted alkoxy, optionally substituted C₁₋₁₀ alkyl,haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, carboxyalkyl,nitro, cyano, acylamido, hydroxy, thiol, acyloxy, azido, carboxy,ethylenedioxo, carbonylamido or optionally substituted alkylthiol;

R₇-R₁₀ independently are hydrogen, halo, optionally substituted amino,alkoxy, C₁₋₁₀ alkyl, haloalkyl, aryl, heteroaryl, a carbocyclic group, aheterocyclic group, alkenyl, alkynyl, arylalkyl, arylalkenyl,arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl,carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, hydroxyalkoxy,aminoalkyl, aminoalkoxy, carboxyalkyl, carboxyalkoxy, nitro, cyano,acylamido, aminocarbonyl, hydroxy, thiol, acyloxy, azido, carboxy,carbonylamido, alkylsulfonyl, aminosulfonyl, dialkylaminosulfonyl,alkylsulfiniyl, alkylthiol, or substituted carbonyl;

R₁₁ is an optionally substituted amino, hydrazine, alkoxy, C₁₋₁₀ alkyl,haloalkyl, aryl, heteroaryl, carbocyclic group, heterocyclic group,alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl,heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl,hydroxyalkyl, hydroxyalkoxy, aminoalkyl, aminoalkoxy, carboxyalkyl,carboxyalkoxy, acylamido, hydroxy, thiol, acyloxy, carbonylamido, oralkylthiol.

One group of preferred compounds of Formula II includes compoundswherein R₇, R₈, R₉ or R₁₀ is hydrogen or halo, preferably fluoro.Another group of preferred compounds of Formula II includes compoundswherein R₁ or R₂ is hydrogen, fluoro, chloro, bromo or methyl. Anothergroup of preferred compounds of Formula II includes compounds wherein R₄is hydrogen, fluoro, methyl, methoxy or hydroxy. Another group ofpreferred compounds of Formula II includes compounds wherein R₁₁ is anoptionally substituted amino, more preferably substituted piperazine orpiperidine.

One group of preferred compounds of the present invention arerepresented by Formula III:

or pharmaceutically acceptable salts or prodrugs thereof, wherein:

R₁-R₄ independently are hydrogen, halo, optionally substituted amino,optionally substituted alkoxy, optionally substituted C₁₋₁₀ alkyl,haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, carboxyalkyl,nitro, cyano, acylamido, hydroxy, thiol, acyloxy, azido, carboxy,ethylenedioxo, carbonylamido or optionally substituted alkylthiol;

R₇-R₁₀ independently are hydrogen, halo, optionally substituted amino,alkoxy, C₁₋₁₀ alkyl, haloalkyl, aryl, heteroaryl, a carbocyclic group, aheterocyclic group, alkenyl, alkynyl, arylalkyl, arylalkenyl,arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl,carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, hydroxyalkoxy,aminoalkyl, aminoalkoxy, carboxyalkyl, carboxyalkoxy, nitro, cyano,acylamido, aminocarbonyl, hydroxy, thiol, acyloxy, azido, carboxy,carbonylamido, alkylsulfonyl, aminosulfonyl, dialkylaminosulfonyl,alkylsulfiniyl, alkylthiol, or substituted carbonyl;

R₁₂ is an optionally substituted C₁₋₁₀ alkyl, haloalkyl, cycloalkyl,aryl, heteroaryl, carbocyclic group, heterocyclic group, alkenyl,alkynyl, acyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl,heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl,hydroxyalkyl, aminoalkyl, carboxyalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,heterocyclocarbonyl, aminocarbonyl, alkylsulfonyl, cycloalkylsulfonyl oraminosulfonyl.

In one preferred embodiment, one group of preferred compounds of FormulaIII includes compounds wherein R₁₂ is selected from the group consistingof cycloalkyl, aryl, heteroaryl, carbocyclic group, heterocyclic group,arylalkyl, heteroarylalkyl, carbocycloalkyl, heterocycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl orheterocyclocarbonyl. Another group of preferred compounds of Formula IIIincludes compounds wherein R₁ or R₂ is hydrogen, fluoro, chloro, bromoor methyl; R₄ is hydrogen, fluoro, methoxy or hydroxy; R₇, R₈, R₉ or R₁₀is hydrogen or fluoro.

Exemplary preferred compounds of Formulae I, II and III include, withoutlimitation:

-   1-(3-Methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-Carboxybenzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-Cyclohexylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-([1,2,4]Triazolo[4,3-b]pyridazin-6-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-Ethylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-Benzoylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(4-Fluorobenzoyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(4-Chlorobenzoyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(4-Bromobenzoyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(4-Methoxybenzoyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Tetrahydro-2H-pyran-4-yl)carbonylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclopropylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Ethylsulfonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-Acetylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-Phenylpiperidine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-Phenylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Pyrazin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(4-Fluoro-3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-Carboxy-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;-   1-(4-Fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(4-Fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Benzo[d]isothiazol-3-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Piperidin-1-yl)piperidine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Pyridin-4-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclobutylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Furan-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Furan-3-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Thiophene-3-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Pyridine-3-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Pyridine-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Pyridine-4-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-Phenoxypiperidine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclopropylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;-   1-(4-Fluoro-3-(4-(pyrazin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Benzo[d]isothiazol-3-yl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclobutylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-Benzoylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;-   1-(4-Fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(4-Fluoro-3-(4-(furan-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;-   1-(6-Fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(6-Fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(6-Fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclobutylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;-   1-(6-Fluoro-3-(4-(furan-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(6-Chloro-3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(6-Chloro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(6-Chloro-3-(4-(cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(6-Chloro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(2-Chloro-3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(2-Chloro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(2-Fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)-2-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;-   1-(5-Fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)-5-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;-   1-(4-Chloro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(4-Chloro-3-(4-(cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-((2-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)furan-5-yl)methyl)quinazoline-2,4(1H,3H)-dione;-   1-((2-(4-(Benzo[d]isothiazol-3-yl)piperazine-1-carbonyl)furan-5-yl)methyl)quinazoline-2,4(1H,3H)-dione;-   1-((2-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)pyridin-6-yl)methyl)quinazoline-2,4(1H,3H)-dione;-   1-((2-(4-(Pyridin-2-yl)piperazine-1-carbonyl)pyridin-6-yl)methyl)quinazoline-2,4(1H,3H)-dione;-   1-((2-(4-(Pyrimidin-2-yl)piperazine-1-carbonyl)pyridin-6-yl)methyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Thiazol-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclohexylmethyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclopentylmethyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclohexylsulfonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)-7-fluoroquinazoline-2,4(1H,3H)-dione;-   7-Fluoro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)-7-methylquinazoline-2,4(1H,3H)-dione;-   7-Methyl-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   6-Methyl-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)-6-methylquinazoline-2,4(1H,3H)-dione;-   1-(4-Fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-6-methylquinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-6-methylquinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-6-methylquinazoline-2,4(1H,3H)-dione;-   6-Bromo-1-(3-(4-(cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   6-Bromo-1-(3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   6-Bromo-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)-6-nitroquinazoline-2,4(1H,3H)-dione;-   6-Nitro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)-6-nitroquinazoline-2,4(1H,3H)-dione;-   1-(4-(4-Benzoylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(4-(4-(Pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(4-(4-(4-Methoxybenzoyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(4-(4-(4-Fluorobenzoyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(4-(4-(Pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(4-(4-(4-Bromobenzoyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(4-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   5-Chloro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   5-Chloro-1-(3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   5-Chloro-1-(3-(4-(cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   5-Chloro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   5-Chloro-1-(3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;-   5-Chloro-1-(3-(4-(cyclohexylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;-   5-Chloro-1-(4-fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   5-Chloro-1-(4-fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   5-Chloro-1-(3-(4-(cyclohexylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;-   5-Chloro-1-(3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;-   5-Chloro-1-(6-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   6-Chloro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   6-Chloro-1-(3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   6-Chloro-1-(3-(4-(cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   6-Chloro-1-(3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   6-Chloro-1-(3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   6-Chloro-1-(3-(4-(cyclobutylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   6-Chloro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   6-Chloro-1-(3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;-   6-Chloro-1-(3-(4-(cyclohexylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;-   6-Chloro-1-(4-fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   6-Chloro-1-(4-fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   6-Chloro-1-(3-(4-(cyclopropylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline)-2,4(1H,3H)-dione;-   6-Chloro-1-(6-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   6-Chloro-1-(3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;-   6-Chloro-1-(3-(4-(cyclohexylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;-   6-Chloro-1-(6-fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   5-Fluoro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;-   5-Fluoro-1-(3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   5-Fluoro-(1-(3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline)-2,4(1H,3H)-dione;-   5-Fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;-   5-Fluoro-1-(4-fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   5-Fluoro-1-(4-fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-Benzoylpiperazine-1-carbonyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)-8-fluoroquinazoline-2,4(1H,3H)-dione;-   6-Fluoro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   6-Fluoro-1-(3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   6-Fluoro-1-(3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione;-   6-Fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   6-Fluoro-1-(4-fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   6-Fluoro-1-(4-fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione;-   6-Fluoro-1-(6-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   6-Fluoro-1-(6-fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   6-Fluoro-1-(6-fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione;-   5-Fluoro-1-(6-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   5-Fluoro-1-(6-fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   5-Fluoro-1-(6-fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;-   5-Methyl-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)-5-methylquinazoline-2,4(1H,3H)-dione;-   7-Chloro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   7-Chloro-1-(3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclopropylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-5-fluoroquinazoline)-2,4(1H,3H)-dione;-   6-Chloro-(1-(3-(4-benzoylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline)-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclobutylcarbonyl)piperazine-1-carbonyl)benzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclobutylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;-   6-Chloro-1-(3-(4-(cyclobutylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;-   5-Chloro-1-(3-(4-(cyclobutylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;-   6-Chloro-1-(3-(4-(cyclobutylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;-   5-Chloro-1-(3-(4-(cyclobutylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;-   5-Chloro-1-(6-fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   5-Fluoro-1-(4-fluoro-3-(4-(furan-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   5-Chloro-1-(6-fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   6-Chloro-1-(6-fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   6-Chloro-1-(5-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   5-Fluoro-1-(5-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-Cyclopentylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclopropylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclobutylcarbonyl)piperazine-1-carbonyl)benzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclobutylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione;-   1-(3-(4-Benzoylpiperazine-1-carbonyl)-4-fluorobenzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclobutylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclobutylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione;-   5-Fluoro-1-(6-fluoro-3-(4-(furan-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   6-Fluoro-1-(4-fluoro-3-(4-(furan-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   6-Fluoro-1-(5-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(6-Chloro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione;-   6-Fluoro-1-(4-fluoro-3-(4-(thiazol-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   5-Fluoro-1-(4-fluoro-3-(4-(thiazol-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(4-Fluoro-3-(4-(thiazol-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclohexylcarbamoyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(4-Fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione    hydrochloride;-   5-Fluoro1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione    hydrochloride;-   1-(3-(4-(Pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione    hydrochloride;-   1-(3-((4-(Pyridin-2-yl)piperazin-1-yl)methyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(Naphthalen-2-yl)acetamidobenzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(3,4-Dimethoxyphenyl)acetamidobenzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-([1,2,4]Triazolo[4,3-a]pyridine-6-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   6-Fluoro-1-((2-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)pyridin-6-yl)methyl)quinazoline-2,4(1H,3H)-dione;-   5-Fluoro-1-(4-fluoro-3-(4-methoxybenzylcarbamoyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(3-Chlorobenzylcarbamoyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;-   1-(3-(Benzylcarbamoyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;-   5-Methoxy-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   6-Methoxy-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(5-Bromopyrimidin-2-aminocarbamoyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione;-   6,7-Ethylenedioxo-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   5-Fluoro-1-(6-methoxy-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   7-Methoxy-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   5-Fluoro-1-(4-fluoro-3-(4-(tetrahydrofuran-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   5-Fluoro-1-(4-nitro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-Cyclohexylpiperazine-1-carbonyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;-   5-Fluoro-1-(4-fluoro-3-(4-phenylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   5-Fluoro-1-(4-fluoro-3-(4-phenylpiperidine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(4-Bromo-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;-   6,7-Methylenedioxo-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(3-(4-(Cyclohexylmethyl)piperazine-1-carbonyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;-   8-Fluoro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   6-Amino-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   1-(2-(4-(Pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   8-Chloro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   8-Methyl-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   8-Methoxy-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;-   8-Hydroxy-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;

and pharmaceutically acceptable salts or prodrugs thereof.

The term “alkyl” as employed herein by itself or as part of anothergroup refers to both straight and branched chain radicals of up to tencarbons. Useful alkyl groups include straight-chained and branched C₁₋₁₀alkyl groups, more preferably C₁₋₆ alkyl groups. Typical C₁₋₁₀ alkylgroups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,tert-butyl, 3-pentyl, hexyl and octyl groups, which may be optionallysubstituted.

The term “alkenyl” as employed herein by itself or as part of anothergroup means a straigh or branched chain radical of 2-10 carbon atoms,unless the chain length is limited thereto, including at least onedouble bond between two of the carbon atoms in the chain. Typicalalkenyl groups include ethenyl, 1-propenyl, 2-propenyl,2-methyl-1-propenyl, 1-butenyl and 2-butenyl.

The term “alkynyl” is used herein to mean a straight or branched chainradical of 2-10 carbon atoms, unless the chain length is limitedthereto, wherein there is at least one triple bond between two of thecarbon atoms in the chain. Typical alkynyl groups include ethynyl,1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl and 2-butynyl.

Useful alkoxy groups include oxygen substituted by one of the C₁₋₁₀alkyl groups mentioned above, which may be optionally substituted.Alkoxy substituents include, without limitation, halo, morpholino, aminoincluding alkylamino and dialkylamino, and carboxy including estersthereof.

Useful alkylthio groups include sulfur substituted by one of the C₁₋₁₀alkyl groups mentioned above, which may be optionally substituted. Alsoincluded are the sulfoxides and sulfones of such alkylthio groups.

Useful amino and optionally substituted amino groups include —NH₂,—NHR₁₅ and —NR₁₅R₁₆, wherein R₁₅ and R₁₆ are optionally substitutedC₁₋₁₀ alkyl, cycloalkyl, aryl, heteroaryl, or amino; or R₁₅ and R₁₆ arecombined with the N to form a 5-8 membered heterocyclic ring structure,such as a piperidine; or R₁₅ and R₁₆ are combined with the N and anadditional N or O atom to form a 5-8 membered heterocyclic ring, such asa piperazine, which are optionally substituted.

The groups as described herein, such as alkyl, alkoxy, alkylthio,alkenyl, alkynyl, cycloalkyl, carbonyl, carbocyclic and heterocyclicgroups, aryl, arylalkyl, arylalkenyl, arylalkynyl and heteroaryl andheteroarylalkyl groups, may be optionally substituted. Generally, theterm “optionally substituted” used herein indicates that the group thatis “optionally substitutited” may be optionally substituted by one ormore (such as 1, 2, 3, or 4) substituents selected from the groupconsisting of halo, hydroxy, carboxyl, amino, nitro, cyano, C₁-C₆acylamino, C₁-C₆ acyloxy, C₁-C₆ alkoxy, aryloxy, alkylthio, C₁-C₆ alkyl,C₆-C₁₀ aryl, C₃-C₈ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀aryl(C₂-C₆)alkenyl, C₆-C₁₀ aryl(C₂-C₆)alkynyl, saturated and unsaturatedheterocyclic and heteroaryl, methylenedioxy, C₁-C₆ haloalkyl, C₆C₆-C₁₀aryl(C₁-C₆)alkyl, C₁-C₆ hydroxyalkyl, ureido, thiol, azido, C₁-C₆alkoxy, carbonyl, di(C₁₋₁₀ alkyl)amino, alkylsulfonyl, aminosulfonyl,dialkylaminosulfonyl, and alkylsulfiniyl, and the like. The substituentitself may also be optionally substituted.

Optional substituents on the alkyl, alkoxy, alkylthio, alkenyl, alkynyl,cycloalkyl, carbonyl, carbocyclic and heterocyclic groups may be one ormore (such as 1, 2, 3, or 4) groups selected from the group consistingof halo, hydroxy, carboxyl, amino, nitro, cyano, C₁-C₆ acylamino, C₁-C₆acyloxy, C₁-C₆ alkoxy, aryloxy, alkylthio, C₆-C₁₀ aryl, C₃-C₈cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ aryl(C₂-C₆)alkenyl,C₆-C₁₀ aryl(C₂-C₆)alkynyl, saturated and unsaturated heterocyclic andheteroaryl.

Optional substituents on the aryl, arylalkyl, arylalkenyl, arylalkynyland heteroaryl and heteroarylalkyl groups may be one or more (such as 1,2, 3, or 4) groups selected from the group consisting of halo,methylenedioxy, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, C₃-C₈ cycloalkyl, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ aryl(C₁-C₆)alkyl, C₆-C₁₀aryl(C₂-C₆)alkenyl, C₆-C₁₀ aryl(C₂-C₆)alkynyl, C₁-C₆ hydroxyalkyl,nitro, amino, ureido, cyano, C₁-C₆ acylamino, hydroxy, thiol, C₁-C₆acyloxy, azido, C₁-C₆ alkoxy, carbonyl, carboxy, di(C₁₋₁₀ alkyl)amino,alkylsulfonyl, aminosulfonyl, dialkylaminosulfonyl, and alkylsulfiniyl.

The term “aryl” as employed herein by itself or as part of another grouprefers to monocyclic, bicyclic or tricyclic aromatic groups containingfrom 6 to 14 carbons in the ring portion.

Useful aryl groups include C₆₋₁₄ aryl, preferably C₆₋₁₀ aryl. TypicalC₆₋₁₄ aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl,indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups.

The term “carbocycle” as employed herein include cycloalkyl andpartially saturated carbocyclic groups. Useful cycloalkyl groups areC₃₋₈ cycloalkyl. Typical cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Useful saturated or partially saturated carbocyclic groups arecycloalkyl groups as described above, as well as cycloalkenyl groups,such as cyclopentenyl, cycloheptenyl and cyclooctenyl.

Useful halo or halogen groups include fluorine, chlorine, bromine andiodine.

The term “arylalkyl” is used herein to mean any of the above-mentionedC₁₋₁₀ alkyl groups substituted by any of the above-mentioned C₆₋₁₄ arylgroups. Preferably the arylalkyl group is benzyl, phenethyl ornaphthylmethyl.

The term “arylalkenyl” is used herein to mean any of the above-mentionedC₂₋₁₀ alkenyl groups substituted by any of the above-mentioned C₆₋₁₄aryl groups.

The term “arylalkynyl” is used herein to mean any of the above-mentionedC₂₋₁₀ alkynyl groups substituted by any of the above-mentioned C₆₋₁₄aryl groups.

The term “aryloxy” is used herein to mean oxygen substituted by one ofthe above-mentioned C₆₋₁₄ aryl groups, which may be optionallysubstituted. Useful aryloxy groups include phenoxy and 4-methylphenoxy.

The term “arylalkoxy” is used herein to mean any of the above mentionedC₁₋₁₀ alkoxy groups substituted by any of the above-mentioned arylgroups, which may be optionally substituted. Useful arylalkoxy groupsinclude benzyloxy and phenethyloxy.

Useful haloalkyl groups include alkyl groups, such as C₁₋₁₀ alkyl, orpreferably C₁₋₆ alkyl substituted by one or more fluorine, chlorine,bromine or iodine atoms, e.g., fluoromethyl, difluoromethyl,trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, chloromethyl,chlorofluoromethyl and trichloromethyl groups.

Useful acylamino (acylamido) groups are any C₁₋₆ acyl (alkanoyl)attached to an amino nitrogen, e.g., acetamido, chloroacetamido,propionamido, butanoylamido, pentanoylamido and hexanoylamido, as wellas aryl-substituted C₁₋₆ acylamino groups, e.g., benzoylamido, andpentafluorobenzoylamido. Useful acyl includes C₁₋₆ acyl, such as acetyl.

Useful acyloxy groups are any C₁₋₆ acyl (alkanoyl) attached to an oxy(—O—) group, e.g., formyloxy, acetoxy, propionoyloxy, butanoyloxy,pentanoyloxy and hexanoyloxy.

The term heterocycle (heterocyclic group) is used herein to mean asaturated or partially saturated 3-7 membered monocyclic, or 7-10membered bicyclic ring system, which consists of carbon atoms and one tofour heteroatoms independently selected from the group consisting of O,N, and S, wherein the nitrogen and sulfur heteroatoms can be optionallyoxidized, the nitrogen can be optionally quaternized. The term alsoincludes any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The heterocyclic ring ofheterocycle can be substituted on carbon or on a nitrogen atom if theresulting compound is stable.

Useful saturated or partially saturated heterocyclic groups includetetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl,imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl,morpholinyl, isochromanyl, chromanyl, pyrazolidinyl pyrazolinyl,tetronoyl and tetramoyl groups, which are optionally substituted.

The term “heteroaryl” as employed herein refers to groups having 5 to 14ring atoms; 6, or 14 π electrons shared in a cyclic array; andcontaining, as ring atom, carbon atoms and 1-3 heteroatoms selected fromoxygen, nitrogen and sulfur.

Useful heteroaryl groups include thienyl (thiophenyl),benzo[d]isothiazol-3-yl, benzo[b]thienyl, naphtho[2,3-b]thienyl,thianthrenyl, furyl (furanyl), pyranyl, isobenzofuranyl, chromenyl,xanthenyl, phenoxanthiinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl(pyridinyl), including without limitation 2-pyridyl, 3-pyridyl, and4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl,3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl,quinolyl, phthalzinyl, naphthyridinyl, quinozalinyl, cinnolinyl,pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acrindinyl,perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl,isoxazolyl, furazanyl, phenoxazinyl, 1,4-dihydroquinoxaline-2,3-dione,7-aminoisocoumarin, pyrido[1,2-c]pyrimidin-4-one,tetrahydrocyclopenta[c]pyrazol-3-yl, pyrazolo[1,5-c]pyrimidinyl,benzoisoxazolyl such as 1,2-benzoisoxazol-3-yl, benzimidazolyl,2-oxindolyl, thiadiazolyl, and 2-oxobenzimidazolyl. Where the heteroarylgroup contains a nitrogen atom in a ring, such nitrogen atom may be inthe form of an N-oxide, e.g., a pyridyl N-oxide, pyrazinyl N-oxide andpyrimidinyl N-oxide.

The term “heteroaryloxy” is used herein to mean oxygen substituted byone of the above-mentioned heteroaryl groups, which may be optionallysubstituted. Useful heteroaryloxy groups include pyridyloxy,pyrazinyloxy, pyrrolyloxy, pyrazolyloxy, imidazolyloxy andthiophenyloxy.

The term “heteroarylalkoxy” is used herein to mean any of theabove-mentioned C₁₋₁₀ alkoxy groups substituted by any of theabove-mentioned heteroaryl groups, which may be optionally substituted.

Some of the compounds of the present invention may exist asstereoisomers including optical isomers. The invention includes allstereoisomers and both the racemic mixtures of such stereoisomers aswell as the individual enantiomers that may be separated according tomethods that are well known to those of ordinary skill in the art.

Examples of pharmaceutically acceptable addition salts include inorganicand organic acid addition salts, such as hydrochloride, hydrobromide,phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate,mandelate and oxalate; and inorganic and organic base addition saltswith bases, such as sodium hydroxy, Tris(hydroxymethyl)aminomethane(TRIS, tromethane) and N-methyl-glucamine.

Examples of prodrugs of the compounds of the invention include thesimple esters of carboxylic acid containing compounds (e.g., thoseobtained by condensation with a C₁₋₄ alcohol according to methods knownin the art); esters of hydroxy containing compounds (e.g., thoseobtained by condensation with a C₁₋₄ carboxylic acid, C₃₋₆ dioic acid oranhydride thereof, such as succinic and fumaric anhydrides according tomethods known in the art); imines of amino containing compounds (e.g.,those obtained by condensation with a C₁₋₄ aldehyde or ketone accordingto methods known in the art); carbamate of amino containing compounds,such as those described by Leu, et. al., (J. Med. Chem. 42:3623-3628(1999)) and Greenwald, et al., (J. Med. Chem. 42:3657-3667 (1999)); andacetals and ketals of alcohol containing compounds (e.g., those obtainedby condensation with chloromethyl methyl ether or chloromethyl ethylether according to methods known in the art).

The compounds of this invention may be prepared using methods known tothose skilled in the art, or the novel methods of this invention.Specifically, the compounds of this invention with Formula I, II or IIIcan be prepared as illustrated by the exemplary reaction in Scheme 1(Shunsuke Goto et al. Organic Process Research & Development, 2003, 7,700-706). Reaction of quinazoline-2,4(1H,3H)-dione withhexamethyldisilazane (HMDS) in toluene in the presence of sulfuric acidproduced the intermediate 2,4-di(trimethylsiloxy)quinazoline. Reactionof 2,4-di(trimethylsiloxy)quinazoline with a substituted alkyl3-(halomethyl)benzoate, such as methyl 3-(bromomethyl)benzoate in DMF,followed by treatment with 1,4-dioxane and methanol, produced1-(3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione. Treatment ofthe ester with NaOH in water-methanol produced1-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione. Coupling of the acidwith a substituted amine, such as 1-(pyridin-2-yl)piperazine, in thepresence of coupling agents, such as2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIPEA) in DMF,produced the targeted compound1-(3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione.

Other related compounds can be prepared similarly. For example,replacement of methyl 3-(bromomethyl)benzoate with methyl6-(bromomethyl)pyridine-2-carboxylate produced the targeted compound1-((2-(4-(pyridin-2-yl)piperazine-1-carbonyl)pyridin-6-yl)methyl)quinazoline-2,4(1H,3H)-dione.Replacement of methyl 3-(bromomethyl)benzoate with ethyl5-(chloromethyl)furan-2-carboxylate produced the targeted compound1-((2-(4-cyclopentylcarbonylpiperazine-1-carbonyl)furan-5-yl)methyl)quinazoline-2,4(1H,3H)-dione.Replacement of methyl 3-(bromomethyl)benzoate with methyl3-(2-bromoethyl)benzoate produced the targeted compound1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)phenethyl)quinazoline-2,4(1H,3H)-dione.

For quinazoline-2,4(1H,3H)-dione with a substituent in the 8-position,such as 8-chloro quinazoline-2,4(1H,3H)-dione, reaction withhexamethyldisilazane (HMDS) followed by treatment of the intermediate8-chloro-2,4-di(trimethylsiloxy)quinazoline with methyl3-(bromomethyl)benzoate produced a mixture of1-(3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione and3-(3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione. The mixture canbe separated, hydrolyzed, and coupled with a substituted amine toproduce the 1-substituted compound and 3-substituted compound,respectively. Alternatively, the 3-substituted compound also can beprepared from reaction of quinazoline-2,4(1H,3H)-dione with methyl3-(bromomethyl)benzoate and K₂CO₃ in DMF, followed by hydrolysis andcoupling of the acid with a substituted amine.

Compounds of this invention can be prepared as illustrated by theexemplary reaction in Scheme 2. Reaction of the intermediate2,4-di(trimethylsiloxy)quinazoline with a substituted alkyl3-(halomethyl)benzoate, such as methyl 5-(bromomethyl)-2-fluorobenzoatein DMF, followed by treatment with 1,4-dioxane and methanol, produced1-(4-fluoro-3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione.Treatment of the ester with NaOH in water-methanol produced1-(3-carboxy-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione. Coupling ofthe acid with a substituted amine, such as1-cyclopentylcarbonylpiperazine, in the presence of coupling agents,such as HATU and DIPEA in DMF, produced the targeted compound1-(3-(4-cyclopentylcarbonylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione.

Other related compounds can be prepared similarly. For example,replacement of quinazoline-2,4(1H,3H)-dione with a substitutedquinazoline-2,4(1H,3H)-dione, such as5-fluoroquinazoline-2,4(1H,3H)-dione, which can be prepared fromreaction of 2-amino-6-fluorobenzoic acid with potassium cyanate,produced the targeted compound1-(3-(4-cyclopentylcarbonylpiperazine-1-carbonyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione.Replacement of methyl 5-(bromomethyl)-2-fluorobenzoate with anothersubstituted methyl 3-(bromomethyl)benzoate, such as methyl3-(bromomethyl)-4-fluorobenzoate, produced the targeted compound1-(3-(4-cyclopentylcarbonylpiperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione.Replacement of 1-cyclopentylcarbonylpiperazine with another substitutedamine, such as 1-(pyrimidin-2-yl)piperazine, produced the targetedcompound1-(−4-fluoro-3-(4-(pyrimidin-2-yl)carbonylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione.

The compounds of this invention can be prepared as illustrated by theexemplary reaction in Scheme 3. Reaction of 2-amino-3-methylbenzoic acidwith triphosgene in THF produced8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione, which was treated withtert-butylamine and DMAP in DMF to produce2-amino-N-tert-butyl-3-methylbenzamide. Reaction of the benzamide withCDI in THF produced 3-tert-butyl-8-methylquinazoline-2,4(1H,3H)-dione,which was reacted with methyl 3-(bromomethyl)benzoate and MeONa in DMF,followed by treatment with hydrochloric acid aqueous solution, toproduce 8-methyl-1-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione.Coupling of the acid with 2-(piperazin-1-yl)pyrimidine in the presenceof coupling agents, such as HATU and DIPEA in DMF, produced the targetedcompound8-methyl-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione.

Other related compounds can be prepared similarly. For example,replacement of 2-amino-3-methylbenzoic acid with other substituted2-aminobenzoic acid, such as 2-amino-3-methoxybenzoic acid, produced thetargeted compound8-methoxy-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione.

The 1-phenyl substituted compound can be prepared as illustrated by theexemplary reaction in Scheme 4. Reaction of 2-bromobenzamide with oxalylchloride in DCM, followed by addition of methyl 3-aminobenzoate producedmethyl 3-(3-(2-bromobenzoyl)ureido)benzoate. Reaction of the benzoatewith potassium tert-butoxide in DMF produced1-(3-methoxycarbonylphenyl)quinazoline-2,4(1H,3H)-dione. Hydrolysis ofthe ester with NaOH in water-methanol produced1-(3-carboxyphenyl)quinazoline-2,4(1H,3H)-dione. Coupling of the acidwith 2-(piperazin-1-yl)pyrimidine in the presence of coupling agents,such as HATU and DIPEA in DMF, produced the targeted compound1-(3-(1-(pyrimidin-2-yl)piperazine-4-carbonyl)phenyl)quinazoline-2,4(1H,3H)-dione.

An important aspect of the present invention is the discovery thatcompounds having Formula I, II or III are PARP inhibitors. Therefore,these compounds are useful for the treatment of a variety of clinicalconditions responsive to the inhibition of PARP activity, such ascancer.

The present invention includes a therapeutic method comprisingadministering to a mammal an effective amount of a compound of FormulaI, II or III, or a pharmaceutically acceptable salt or prodrug thereof,wherein said therapeutic method is useful for the treatment of diseasesdue to abnormal PARP activity, such as cancer. Such diseases that can betreated or prevented by the method or pharmaceutical composition of thepresent invention include, but are not limited to, liver cancer,melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocyticleukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma,breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor,cervical carcinoma, testicular carcinoma, soft-tissue sarcoma, primarymacroglobulinemia, bladder carcinoma, chronic granulocytic leukemia,primary brain carcinoma, malignant melanoma, small-cell lung carcinoma,stomach carcinoma, colon carcinoma, malignant pancreatic insulinoma,malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, heador neck carcinoma, osteogenic sarcoma, pancreatic carcinoma, acutegranulocytic leukemia, hairy cell leukemia, neuroblastoma,rhabdomyosarcoma, Kaposi's sarcoma, genitourinary carcinoma, thyroidcarcinoma, esophageal carcinoma, malignant hypercalcemia, cervicalhyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemiavera, essential thrombocytosis, adrenal cortex carcinoma, skin cancer,and prostatic carcinoma.

Compounds of the present invention also are useful for the treatment orprevention of other clinical conditions due to abnormal PARP activity,such as excessive cell death, including central nervous system diseasessuch as stroke and neurodegenerative diseases.

In practicing the therapeutic methods, effective amounts of compositionscontaining therapeutically effective concentrations of the compounds ofFormula I, II or III formulated for oral, intravenous, local or topicalapplication, for the treatment of neoplastic diseases and otherdiseases, are administered to an individual exhibiting the symptoms ofone or more of these disorders. The amounts are effective to ameliorateor eliminate one or more symptoms of the disorders. An effective amountof a compound for treating a particular disease is an amount that issufficient to ameliorate, or in some manner reduce, the symptomsassociated with the disease. Such amount may be administered as a singledosage or may be administered according to a regimen, whereby it iseffective. The amount may cure the disease but, typically, isadministered in order to ameliorate the symptoms of the disease.Typically, repeated administration is required to achieve the desiredamelioration of symptom.

In another embodiment, a pharmaceutical composition comprising acompound of Formula I, II or III or a pharmaceutically acceptable saltthereof, which functions as PARP inhibitor, in combination with apharmaceutically acceptable vehicle, is provided.

Another embodiment of the present invention is directed to a compositioneffective to inhibit neoplasia comprising a compound of Formula I, II orIII, or a pharmaceutically acceptable salt or prodrug thereof, whichfunctions as a PARP inhibitor, in combination with at least one knownanticancer agent or a pharmaceutically acceptable salt thereof. Examplesof known anticancer agents which may be used for combination therapyinclude, but not are limited to alkylating agents, such as busulfan,melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide,bendamustine, cis-platin, mitomycin C, bleomycin, and carboplatin;topoisomerase I inhibitors, such as camptothecin, irinotecan, andtopotecan; topoisomerase II inhibitors, such as doxorubicin, epirubicin,aclarubicin, mitoxantrone, elliptinium and etoposide; RNA/DNAantimetabolites, such as 5-azacytidine, gemcitabine, 5-fluorouracil andmethotrexate; DNA antimetabolites, such as 5-fluoro-2′-deoxy-uridine,fludarabine, nelarabine, ara-C, alanosine, pralatrexate, pemetrexed,hydroxyurea and thioguanine; antimitotic agents, such as colchicine,vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone,cabazitaxel, and docetaxel; antibodies, such as campath, Panitumumab,Ofatumumab, Avastin, Herceptin®, Rituxan®; kinase inhibitors such asimatinib, gefitinib, erlotinib, lapatinib, sorafenib, sunitinib,nilotinib, dasatinib, pazopanib, temsirolimus and everolimus; HDACinhibitors such as vorinostat and romidepsin. Other known anticanceragents which may be used for combination therapy include tamoxifen,letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenictrioxide, zoledronic acid, bortezomib, thalidomide and lenalidomide.

In practicing the methods of the present invention, the compound of theinvention may be administered together with at least one knownanticancer agent as part of a unitary pharmaceutical composition.Alternatively, the compound of the invention may be administered apartfrom at least one known anticancer agent. In one embodiment, thecompound of the invention and at least one known anticancer agent areadministered substantially simultaneously, i.e. the compounds areadministered at the same time or one after the other, so long as thecompounds reach therapeutic levels in the blood at the same time. Inanother embodiment, the compound of the invention and at least one knownanticancer agent are administered according to their individual doseschedule, so long as the compounds reach therapeutic levels in theblood.

Another embodiment of the present invention is directed to a compositioneffective to inhibit neoplasia comprising a bioconjugate of a compounddescribed herein, which functions as a PARP inhibitor, in bioconjugationwith at least one known therapeutically useful antibody, such asHerceptin® or Rituxan®, growth factors, such as DGF, NGF; cytokines,such as IL-2, IL-4, or any molecule that binds to the cell surface. Theantibodies and other molecules will deliver a compound described hereinto its targets and make it an effective anticancer agent. Thebioconjugates could also enhance the anticancer effect of thetherapeutically useful antibodies, such as Herceptin® or Rituxan®.

Similarly, another embodiment of the present invention is directed to acomposition effective to inhibit neoplasia comprising a compound ofFormula I, II or III, or its pharmaceutically acceptable salt orprodrug, which functions as a PARP inhibitor, in combination withradiation therapy. In this embodiment, the compound of the invention maybe administered at the same time as the radiation therapy isadministered or at a different time.

Yet another embodiment of the present invention is directed to acomposition effective for post-surgical treatment of cancer, comprisinga compound of Formula I, II or III, or its pharmaceutically acceptablesalt or prodrug, which functions as a PARP inhibitor. The invention alsorelates to a method of treating cancer by surgically removing the cancerand then treating the mammal with one of the pharmaceutical compositionsdescribed herein.

Pharmaceutical compositions within the scope of this invention includeall compositions wherein the compounds of the present invention arecontained in an amount that is effective to achieve its intendedpurpose. While individual needs vary, determination of optimal ranges ofeffective amounts of each component is within the skill of the art.Typically, the compounds may be administered to mammals, orally at adose of 0.0025 to 50 mg/kg of body weight, per day, or an equivalentamount of the pharmaceutically acceptable salt thereof, to a mammalbeing treated. Preferably, approximately 0.01 to approximately 10 mg/kgof body weight is orally administered. If a known anticancer agent isalso administered, it is administered in an amount that is effective toachieve its intended purpose. The amounts of such known anticanceragents effective for cancer are well known to those skilled in the art.

The unit oral dose may comprise from approximately 0.01 to approximately50 mg, preferably approximately 0.1 to approximately 10 mg of thecompound of the invention. The unit dose may be administered one or moretimes daily, as one or more tablets, each containing from approximately0.1 to approximately 50 mg, conveniently approximately 0.25 to 10 mg ofthe compound or its solvates.

In a topical formulation, the compound may be present at a concentrationof approximately 0.01 to 100 mg per gram of carrier.

In addition to administering the compound as a raw chemical, thecompounds of the invention may be administered as part of apharmaceutical preparation containing suitable pharmaceuticallyacceptable carriers comprising excipients and auxiliaries, whichfacilitate processing of the compounds into preparations that may beused pharmaceutically. Preferably, the preparations, particularly thosepreparations which may be administered orally and that may be used forthe preferred type of administration, such as tablets, dragees, andcapsules, as well as suitable solutions for administration by injectionor orally, contain from approximately 0.01 to 99 percent, preferablyfrom approximately 0.25 to 75 percent of active compound(s), togetherwith the excipient.

Also included within the scope of the present invention are thenon-toxic pharmaceutically acceptable salts of the compounds of thepresent invention. Acid addition salts are formed by mixing a solutionof the compounds of the present invention with a solution of apharmaceutically acceptable non-toxic acid, such as hydrochloric acid,fumaric acid, maleic acid, succinic acid, acetic acid, citric acid,tartaric acid, carbonic acid, phosphoric acid, oxalic acid, and thelike. Base addition salts are formed by mixing a solution of thecompounds of the present invention with a solution of a pharmaceuticallyacceptable non-toxic base, such as sodium hydroxide, potassiumhydroxide, choline hydroxide, sodium carbonate, Tris, N-methyl-glucamineand the like.

The pharmaceutical compositions of the invention may be administered toany mammal, which may experience the beneficial effects of the compoundsof the invention. Foremost among such mammals are humans and veterinaryanimals, although the invention is not intended to be so limited.

The pharmaceutical compositions of the present invention may beadministered by any means that achieve their intended purpose. Forexample, administration may be by parenteral, subcutaneous, intravenous,intramuscular, intraperitoneal, transdermal, buccal, intrathecal,intracranial, intranasal or topical routes. Alternatively, orconcurrently, administration may be by the oral route. The dosageadministered will be dependent upon the age, health, and weight of therecipient, kind of concurrent treatment, if any, frequency of treatment,and the nature of the effect desired.

The pharmaceutical preparations of the present invention aremanufactured in a manner, which is itself known, e.g., by means ofconventional mixing, granulating, dragee-making, dissolving, orlyophilizing processes. Thus, pharmaceutical preparations for oral usemay be obtained by combining the active compounds with solid excipients,optionally grinding the resulting mixture and processing the mixture ofgranules, after adding suitable auxiliaries, if desired or necessary, toobtain tablets or dragee cores.

Suitable excipients are, in particular: fillers, such as saccharides,e.g. lactose or sucrose, mannitol or sorbitol; cellulose preparationsand/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogenphosphate; as well as binders, such as starch paste, using, e.g., maizestarch, wheat starch, rice starch, potato starch, gelatin, tragacanth,methyl cellulose, hydroxypropylmethylcellulose, sodiumcarboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired,disintegrating agents may be added, such as the above-mentioned starchesand also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar,or alginic acid or a salt thereof, such as sodium alginate. Auxiliariesare, above all, flow-regulating agents and lubricants, e.g., silica,talc, stearic acid or salts thereof, such as magnesium stearate orcalcium stearate, and/or polyethylene glycol. Dragee cores are providedwith suitable coatings which, if desired, are resistant to gastricjuices. For this purpose, concentrated saccharide solutions may be used,which may optionally contain gum arabic, talc, polyvinyl pyrrolidone,polyethylene glycol and/or titanium dioxide, lacquer solutions andsuitable organic solvents or solvent mixtures. In order to producecoatings resistant to gastric juices, solutions of suitable cellulosepreparations, such as acetylcellulose phthalate orhydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs orpigments may be added to the tablets or dragee coatings, e.g., foridentification or in order to characterize combinations of activecompound doses.

Other pharmaceutical preparations, which may be used orally, includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules may contain the active compounds in the form of: granules,which may be mixed with fillers, such as lactose; binders, such asstarches; and/or lubricants, such as talc or magnesium stearate and,optionally, stabilizers. In soft capsules, the active compounds arepreferably dissolved or suspended in suitable liquids, such as fattyoils, or liquid paraffin. In addition, stabilizers may be added.

Suitable formulations for parenteral administration include aqueoussolutions of the active compounds in water-soluble form, e.g.,water-soluble salts and alkaline solutions. In addition, suspensions ofthe active compounds as appropriate oily injection suspensions may beadministered. Suitable lipophilic solvents or vehicles include fattyoils, e.g., sesame oil, or synthetic fatty acid esters, e.g., ethyloleate or triglycerides or polyethylene glycol-400, or cremophor, orcyclodextrins. Aqueous injection suspensions may contain substanceswhich increase the viscosity of the suspension include, e.g., sodiumcarboxymethyl cellulose, sorbitol, and/or dextran. Optionally, thesuspension may also contain stabilizers.

In accordance with one aspect of the present invention, compounds of theinvention are employed in topical and parenteral formulations and areused for the treatment of skin cancer.

The topical compositions of this invention are formulated preferably asoils, creams, lotions, ointments and the like by choice of appropriatecarriers. Suitable carriers include vegetable or mineral oils, whitepetrolatum (white soft paraffin), branched chain fats or oils, animalfats and high molecular weight alcohol (greater than C₁₂). The preferredcarriers are those in which the active ingredient is soluble.Emulsifiers, stabilizers, humectants and antioxidants may also beincluded, as well as agents imparting color or fragrance, if desired.Additionally, transdermal penetration enhancers may be employed in thesetopical formulations. Examples of such enhancers are found in U.S. Pat.Nos. 3,989,816 and 4,444,762.

Creams are preferably formulated from a mixture of mineral oil,self-emulsifying beeswax and water in which mixture of the activeingredient, dissolved in a small amount of an oil, such as almond oil,is admixed. A typical example of such a cream is one which includesapproximately 40 parts water, approximately 20 parts beeswax,approximately 40 parts mineral oil and approximately 1 part almond oil.

Ointments may be formulated by mixing a solution of the activeingredient in a vegetable oil, such as almond oil, with warm softparaffin and allowing the mixture to cool. A typical example of such anointment is one which includes approximately 30% almond oil andapproximately 70% white soft paraffin by weight.

The present invention also includes the use of the compounds of thesubject invention in the manufacture of a medicament for treating orpreventing a disorder responsive to the inhibition of PARP activity in amammal suffering therefrom. The medicament may include, such as thepharmaceutical compositions as described above.

The following examples are illustrative, but not limiting, of the methodand compositions of the present invention. Other suitable modificationsand adaptations of the variety of conditions and parameters normallyencountered in clinical therapy and which are obvious to those skilledin the art are within the spirit and scope of the invention.

EXAMPLES General Remarks

All reagents were of commercial quality. Solvents were dried andpurified by standard methods. Mass spectrum analyses were recorded on aPlatform II (Agilent 6110) quadrupole mass spectrometer fitted with anelectrospray interface. ¹H NMR spectra was recorded at 300 MHz and at300 K, on a Brücker AMX 300 apparatus. Chemical shifts were recorded asparts per million (ppm) downfield from TMS (0.00 ppm), and J couplingconstants were reported in hertz (Hz).

Example 1 1-(3-Methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione

Quinazoline-2,4(1H,3H)-dione (1.0 g, 6.2 mmol), hexamethyldisilazane(HMDS, 2.5 g, 15.4 mmol), and toluene (50 mL) were added into 100 mLtwo-mouth flask. Concentrated sulfuric acid (0.06 g) was added into theflask when stirring. The mixture was refluxed and reacted for 8 h.Toluene and excessive HMDS were removed via evaporation under reducedpressure, thus obtaining an intermediate product2,4-di(trimethylsilyloxy)quinazoline.

The intermediate product 2,4-di(trimethylsilyloxy)quinazoline, methyl3-(bromomethyl)benzoate (2.1 g, 9.2 mmol) and DMF (1 mL) were added inturn into a 50 mL single-mouth flask, and then the temperature wereraised to 115-130° C. and reacted for 3 hours. 1,4-dioxane (6 mL) andmethanol (10 mL) were added after the reaction mixture was cooled to100° C. Then the mixture was refluxed for 30 minutes. The mixture wasfiltered after it was cooled to room temperature. The precipitate waswashed with water (20 mL) and methonal (10 mL), respectively, and driedto give the title compound (1.6 g, 83.7% yield) as white powder. ¹H NMR(DMSO-d₆): 11.76 (s, 1H), 8.00 (dd, J=7.8 and 1.2 Hz, 1H), 7.89 (s, 1H),7.83 (d, J=7.8 Hz, 1H), 7.65-7.43 (m, 3H), 7.25-7.20 (m, 2H), 5.36 (s,2H), 3.80 (s, 3H). MS: m/z 311.1 [M+H]⁺.

Example 2 1-(3-Carboxybenzyl)quinazoline-2,4(1H,3H)-dione

1-(3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione (1.6 g, 5.2mmol), NaOH (0.31 g, 7.7 mmol), water (40 mL) and methanol (40 mL) wereadded into a 250 mL three-mouth flask. The mixture was refluxed andreacted for 3 hours. The methanol was removed via evaporation underreduced pressure after the reaction was finished. The mixture wasadjusted to pH=2-3 by 3N HCl, forming many precipitates. The mixture wasfiltered and the solid was washed by water and methonal. The solids weredried to give the title compound as white solid (1.2 g, 78% yield). ¹HNMR (300 M, DMSO-d₆): 13.09 (brs, 1H), 11.77 (s, 1H), 8.01 (dd, J=7.7and 1.4 Hz, 1H), 7.84-7.80 (m, 2H), 7.66-7.61 (m, 1H), 7.53 (d, J=7.8Hz, 1H), 7.44 (t, J=7.7 Hz, 1H), 7.27-7.21 (m, 2H), 5.36 (s, 2H). MS:m/z 297.1 [M+H]⁺.

Example 31-(3-(4-(Pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

1-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione (0.2 mmol),1-(pyridin-2-yl)piperazine (0.2 mmol),2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU, 0.26 mmol), N,N-diisopropylethylamine (DIPEA,0.4 mmol) and DMF (5 mL) were added into a 50 mL two-mouth flask. Theobtained mixture was stirred at room temperature for 3 hours. To themixture was added 50 mL of water and it was extracted by dichloromethane(DCM, 50 mL×2). The organic layer was washed by 1N HCl (50 mL×2) andsaturated NaCl aquenous solution (50 mL×2), dried with anhydrous sodiumsulphate, and evaporated under reduced pressure to give the crudeproduct. The crude product was purified by column chromatography (ethylacetate) to give the title compound as white solid (7.7 mg, 8.6% yield).¹H NMR (DMSO-d₆): 11.69 (s, 1H), 8.09 (dd, J=5.0 and 1.7 Hz, 1H), 7.99(dd, J=8.0 and 1.7 Hz, 1H), 7.64 (t, J=7.1 Hz, 1H), 7.53 (t, J=7.8 Hz,1H), 7.40-7.21 (m, 6H), 6.77 (d, J=8.7 Hz, 1H), 6.64 (dd, J=7.1 and 5.0Hz, 1H), 5.34 (s, 2H), 3.40-3.20 (m, 8H). MS: m/z 442.3 [M+H]⁺.

The following compounds were prepared from1-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione and the correspondingsubstituted piperazine or piperidine using a procedure similar to thosedescribed for the synthesis of compound of Example 3.

Example 41-(3-(4-(Pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

White solid. ¹H NMR (DMSO-d₆): 11.71 (s, 1H), 8.36 (d, J=4.8 Hz, 2H),8.01 (d, J=6.9 Hz, 1H), 7.67-7.61 (m, 1H), 7.42-7.24 (m, 6H), 6.65 (t,J=4.8 Hz, 1H), 5.35 (s, 2H), 3.40-3.20 (m, 8H). MS: m/z 443.3 [M+H]⁺.

Example 51-(3-(4-Cyclohexylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

White solid. ¹H NMR (DMSO-d₆): 11.74 (s, 1H), 8.00 (d, J=7.8 Hz, 1H),7.62 (t, J=7.5 Hz, 1H), 7.43-7.38 (m, 2H), 7.26-7.20 (m, 4H), 5.33 (s,2H), 3.40-3.20 (m, 4H), 2.21-2.15 (m, 4H), 1.96-1.70 (m, 5H), 1.21-1.08(m, 6H). MS: m/z 447.3 [M+H]⁺.

Example 61-(3-(4-([1,2,4]Triazolo[4,3-b]pyridazin-6-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

White solid. ¹H NMR (DMSO-d₆): 11.73 (s, 1H), 9.24 (s, 1H), 8.12 (d,J=10.2 Hz, 1H), 8.02 (d, J=7.8 Hz, 1H), 7.66 (t, J=6.9 Hz, 1H),7.42-7.24 (m, 7H), 5.36 (s, 2H), 3.40-3.20 (m, 8H). MS: m/z 483.3[M+H]⁺.

Example 71-(3-(4-Ethylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

White solid. ¹H NMR (DMSO-d₆): 11.72 (s, 1H), 8.01 (dd, J=7.8 and 1.2Hz, 1H), 7.63 (t, J=8.0 Hz, 1H), 7.42-7.38 (m, 2H), 7.26-7.23 (m, 4H),5.34 (s, 2H), 3.40-3.20 (m, 4H), 2.35-2.29 (m, 6H), 0.97 (t, J=7.1 Hz,3H). MS: m/z 393.2 [M+H]⁺.

Example 81-(3-(4-Benzoylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

White solid. ¹H NMR (DMSO-d₆): 11.71 (s, 1H), 7.97 (d, J=8.1 Hz, 1H),7.60-7.56 (m, 1H), 7.45-7.18 (m, 11H), 5.34 (s, 2H), 3.40-3.20 (m, 8H).MS: m/z 469.3 [M+H]⁺.

Example 91-(3-(4-(4-Fluorobenzoyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

White solid. ¹H NMR (DMSO-d₆): 11.71 (s, 1H), 7.99 (d, J=7.8 Hz, 1H),7.60-7.19 (m, 1H), 5.34 (s, 2H), 3.60-3.20 (m, 8H). MS: m/z 487.3[M+H]⁺.

Example 101-(3-(4-(4-Chlorobenzoyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

White solid. ¹H NMR (DMSO-d₆): 11.73 (s, 1H), 7.98-7.97 (m, 1H),7.63-7.57 (m, 1H), 7.48-7.19 (m, 10H), 5.33 (s, 2H), 3.75-3.15 (m, 8H).MS: m/z 503.2, 505.2 [M+H]⁺.

Example 111-(3-(4-(4-Bromobenzoyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

White solid. ¹H NMR (DMSO-d₆): 11.74 (s, 1H), 8.02-7.95 (m, 2H),7.68-7.59 (m, 2H), 7.40-7.15 (m, 8H), 5.35 (s, 2H), 3.40-3.20 (m, 8H).MS: m/z 547.2 [M+H]⁺.

Example 121-(3-(4-(4-Methoxybenzoyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

White solid. ¹H NMR (DMSO-d₆): 11.73 (s, 1H), 7.99 (d, J=7.2 Hz, 1H),7.70-7.50 (m, 1H), 7.40-7.29 (m, 6H), 7.21-7.18 (m, 2H), 6.99-6.96 (m,2H), 5.33 (s, 2H), 3.77 (s, 3H), 3.56-3.15 (m, 8H). MS: m/z 499.3[M+H]⁺.

Example 131-(3-(4-(Tetrahydro-2H-pyran-4-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

White solid. ¹H NMR (DMSO-d₆): 11.74 (s, 1H), 8.02 (d, J=7.5 Hz, 1H),7.65 (t, J=7.8 Hz, 1H), 7.45-7.38 (m, 2H), 7.32-7.23 (m, 4H), 5.36 (s,2H), 3.86-3.82 (m, 2H), 3.75-3.10 (m, 10H), 2.90-2.80 (m, 1H), 1.64-1.48(m, 4H). MS: m/z 477.3 [M+H]⁺.

Example 141-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

White solid. ¹H NMR (DMSO-d₆): 11.71 (s, 1H), 8.01 (d, J=6.9 Hz, 1H),7.70-7.60 (m, 1H), 7.41-7.39 (m, 2H), 7.30-7.21 (m, 4H), 5.34 (s, 2H),3.70-3.10 (m, 8H), 2.95-2.89 (m, 1H), 1.80-1.40 (m, 8H). MS: m/z 461.3[M+H]⁺.

Example 151-(3-(4-(Cyclopropylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

White solid. ¹H NMR (DMSO-d₆): 11.71 (s, 1H), 8.01 (d, J=6.6 Hz, 1H),7.63 (t, J=7.2 Hz, 1H), 7.41-7.21 (m, 6H), 5.34 (s, 2H), 3.80-3.15 (m,8H), 1.94-1.91 (m, 1H), 0.72-0.69 (m, 4H). MS: m/z 433.2 [M+H]⁺.

Example 161-(3-(4-(Ethylsulfonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

White solid. ¹H NMR (DMSO-d₆): 11.74 (s, 1H), 8.01 (dd, J=7.8 and 1.2Hz, 1H), 7.70-7.55 (m, 1H), 7.45-7.35 (m, 2H), 7.31-7.19 (m, 4H), 5.35(s, 2H), 3.75-3.11 (m, 6H), 3.10-2.90 (m, 4H), 1.20 (t, J=7.4 Hz, 3H).MS: m/z 457.2 [M+H]⁺.

Example 171-(3-(4-Acetylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

White solid. ¹H NMR (DMSO-d₆): 11.71 (s, 1H), 8.01 (d, J=6.6 Hz, 1H),7.63 (t, J=7.2 Hz, 1H), 7.43-7.37 (m, 2H), 7.30-7.21 (m, 4H), 5.34 (s,2H), 3.70-3.10 (m, 8H), 1.93 (s, 3H). MS: m/z 407.2 [M+H]⁺.

Example 181-(3-(4-Phenylpiperidine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

White solid. ¹H NMR (300 M, DMSO-d₆): 11.75 (s, 1H), 7.99 (dd, J=7.8 and1.2 Hz, 1H), 7.61 (t, J=7.2 Hz, 1H), 7.41-7.17 (m, 11H), 5.37 (s, 2H),3.55-3.42 (m, 2H), 3.06-2.99 (m, 1H), 2.78-2.71 (m, 2H), 1.97-1.51 (m,4H). MS: m/z 407.2 [M+H]⁺.

Example 191-(3-(4-Phenylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

White solid. ¹H NMR (300 M, DMSO-d₆): 11.75 (s, 1H), 8.03 (d, J=6.6 Hz,1H), 7.67 (t, J=7.2 Hz, 1H), 7.46-7.39 (m, 2H), 7.34-7.21 (m, 6H),6.93-6.91 (m, 2H), 6.81 (t, J=7.2 Hz, 1H), 5.37 (s, 2H), 3.85-2.85 (m,8H). MS: m/z 441.3 [M+H]⁺.

Example 201-(3-(4-(Pyrazin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

White solid. ¹H NMR (300 M, DMSO-d₆): 11.75 (s, 1H), 8.31 (s, 1H), 8.11(s, 1H), 8.02 (d, J=7.8 Hz, 1H), 7.87 (d, J=2.7 Hz, 1H), 7.67 (t, J=7.2Hz, 1H), 7.44-7.24 (m, 6H), 5.37 (s, 2H), 3.80-3.25 (m, 8H). MS: m/z443.3 [M+H]⁺.

Example 211-(4-Fluoro-3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione

The title compound was prepared from quinazoline-2,4(1H,3H)-dione andmethyl 5-(bromomethyl)-2-fluorobenzoate using a procedure similar tothose described for the synthesis of compound of Example 1. ¹H NMR(DMSO-d₆): 11.75 (s, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.84 (d, J=6.9 Hz,1H), 7.67-7.55 (m, 2H), 7.32-7.21 (m, 3H), 5.32 (s, 2H), 3.81 (s, 3H).MS: m/z 329.1 [M+H]⁺.

Example 22 1-(3-Carboxy-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

The title compound was prepared from1-(4-fluoro-3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione using aprocedure similar to those described for the synthesis of compound ofExample 2. ¹H NMR (DMSO-d₆): 13.23 (brs, 1H), 11.75 (s, 1H), 8.00 (d,J=7.5 Hz, 1H), 7.80 (dd, J=6.9 and 2.1 Hz, 1H), 7.67-7.54 (m, 2H),7.30-7.21 (m, 3H), 5.31 (s, 2H). MS: m/z 315.3 [M+H]⁺.

The following compounds were prepared from1-(3-carboxy-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione and thecorresponding substituted piperazine using a procedure similar to thosedescribed for the synthesis of compound of Example 3.

Example 231-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

White solid. ¹H NMR (300 M, DMSO-d₆): 11.73 (s, 1H), 8.00 (d, J=6.9 Hz,1H), 7.64 (t, J=7.8 Hz, 1H), 7.43-7.21 (m, 5H), 5.30 (s, 2H), 3.56-2.97(m, 8H), 2.89-2.84 (m, 1H), 1.80-1.40 (m, 8H). MS: m/z 479.3 [M+H]⁺.

Example 241-(4-Fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

White solid. ¹H NMR (300 M, DMSO-d₆): 11.74 (s, 1H), 8.12 (d, J=3.3 Hz,1H), 8.02 (d, J=6.6 Hz, 1H), 7.67 (t, J=8.4 Hz, 1H), 7.58-7.53 (m, 1H),7.47-7.39 (m, 2H), 7.32-7.24 (m, 3H), 6.82 (d, J=8.4 Hz, 1H), 6.67 (t,J=6.9 Hz, 1H), 5.32 (s, 2H), 3.75-3.67 (m, 2H), 3.61-3.53 (m, 2H),3.42-3.37 (m. 2H), 3.28-3.20 (m, 2H). MS: m/z 460.3 [M+H]⁺.

Example 251-(4-Fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

White solid. ¹H NMR (300 M, DMSO-d₆): 11.72 (s, 1H), 8.37 (d, J=4.8 Hz,2H), 8.00 (d, J=7.8 Hz, 1H), 7.65 (t, J=6.8 Hz, 1H), 7.48-7.38 (m, 2H),7.30-7.22 (m, 3H), 6.66 (t, J=4.8 Hz, 1H), 5.31 (s, 2H), 3.70-3.10 (m,8H). MS: m/z 461.3 [M+H]⁺.

The following compounds were prepared from1-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione and the correspondingsubstituted piperazine or piperidine using a procedure similar to thosedescribed for the synthesis of compound of Example 3.

Example 261-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.75 (s, 1H), 8.02 (d, J=7.8 Hz, 1H), 7.64 (t, J=7.2Hz, 1H), 7.50-7.45 (m, 2H), 7.35-7.20 (m, 4H), 5.35 (s, 2H), 3.50-3.10(m, 9H), 1.80-1.25 (m, 10H). MS: m/z 475.3 [M+H]⁺.

Example 271-(3-(4-(Benzo[d]isothiazol-3-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.75 (s, 1H), 8.08-8.06 (m, 2H), 8.01 (d, J=7.8 Hz,1H), 7.87 (s, 1H), 7.67-7.54 (m, 2H), 7.48-7.30 (m, 5H), 7.27-7.20 (m,2H), 5.37 (s, 2H), 3.80-3.31 (m, 8H). MS: m/z 498.3 [M+H]⁺.

Example 281-(3-(4-(Piperidin-1-yl)piperidine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.76 (s, 1H), 8.03 (d, J=7.2 Hz, 1H), 7.65 (t, J=7.8Hz, 1H), 7.42-7.21 (m, 6H), 5.41-5.32 (m, 2H), 3.10-2.60 (m, 9H),1.90-1.30 (m, 10H). MS: m/z 447.3 [M+H]⁺.

Example 291-(3-(4-(Pyridin-4-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.72 (s, 1H), 8.19 (d, J=6.6 Hz, 2H), 8.02 (d, J=6.3Hz, 1H), 7.68-7.63 (m, 1H), 7.46-7.39 (m, 2H), 7.34-7.23 (m, 4H), 6.89(d, J=6.6 Hz, 2H), 5.35 (s, 2H), 3.84-3.31 (m, 8H). MS: m/z 442.3[M+H]⁺.

Example 301-(3-(4-(Cyclobutylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.72 (s, 1H), 8.03 (d, J=6.4 Hz, 1H), 7.66 (t, J=7.8Hz, 1H), 7.46-7.39 (m, 2H), 7.32-7.23 (m, 4H), 5.36 (s, 2H), 3.52-3.31(m, 9H), 2.19-1.75 (m, 6H). MS: m/z 447.3 [M+H]⁺.

Example 311-(3-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.72 (s, 1H), 8.06 (dd, J=8.7 and 6.4 Hz, 1H), 7.95(dd, J=7.8 and 1.5 Hz, 1H), 7.70 (dd, J=9.3 and 2.1 Hz, 1H), 7.64-7.59(m, 1H), 7.46-7.14 (m, 7H), 5.36 (s, 2H), 3.45-3.28 (m, 5H), 2.10-2.04(m, 1H), 1.99-1.94 (m, 3H). MS: m/z 499.3[M+H]⁺.

Example 321-(3-(4-(Thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.70 (s, 1H), 8.00 (dd, J=8.1 and 1.2 Hz, 1H), 7.76(d, J=5.1 Hz, 1H), 7.64-7.59 (m, 1H), 7.44-7.11 (m, 8H), 5.34 (s, 2H),3.81-3.40 (m, 8H). MS: m/z 475.2 [M+H]⁺.

Example 331-(3-(4-(Furan-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.72 (s, 1H), 8.02 (d, J=6.9 Hz, 1H), 7.86 (s, 1H),7.65 (t, J=7.5 Hz, 1H), 7.50-7.15 (m, 6H), 7.00 (d, J=3.3 Hz, 1H),6.70-6.60 (m, 1H), 5.37 (s, 2H), 3.85-3.20 (m, 8H). MS: m/z 459.2[M+H]⁺.

Example 341-(3-(4-(Furan-3-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.71 (s, 1H), 8.15-7.90 (m, 2H), 7.73 (s, 1H), 7.62(t, J=7.5 Hz, 1H), 7.50-7.10 (m, 6H), 6.64 (s, 1H), 5.34 (s, 2H),3.80-3.10 (m, 8H). MS: m/z 459.3 [M+H]⁺.

Example 351-(3-(4-(Thiophene-3-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.70 (s, 1H), 7.99 (d, J=7.5 Hz, 1H), 7.77 (s, 1H),7.63-7.58 (m, 2H), 7.41-7.39 (m, 2H), 7.30-7.28 (m, 2H), 7.22-7.17 (m,3H), 5.34 (s, 2H), 3.81-3.40 (m, 8H). MS: m/z 475.3 [M+H]⁺.

Example 361-(3-(4-(Pyridine-3-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.72 (s, 1H), 8.67 (dd, J=4.8 and 1.5 Hz, 1H), 8.61(s, 1H), 8.01 (d, J=7.2 Hz, 1H), 7.82 (d, J=6.8 Hz, 1H), 7.52-7.20 (m,8H), 5.36 (s, 2H), 3.52-3.31 (m, 8H). MS: m/z 470.3 [M+H]⁺.

Example 371-(3-(4-(Pyridine-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.78 (s, 1H), 8.68 (d, J=4.2 Hz, 1H), 8.20-7.95 (m,2H), 7.68-7.27 (m, 9H), 5.43 (s, 2H), 3.90-3.50 (m, 8H). MS: m/z 470.3[M+H]⁺.

Example 381-(3-(4-(Pyridine-4-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.62 (s, 1H), 8.58 (d, J=4.2 Hz, 2H), 7.91-7.89 (m,1H), 7.57-7.44 (m, 1H), 7.29-7.10 (m, 8H), 5.25 (s, 2H), 3.80-2.75 (m,8H). MS: m/z 470.3 [M+H]⁺.

Example 391-(3-(4-Phenoxypiperidine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.67 (s, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.57 (t, J=7.8Hz, 1H), 7.38-7.30 (m, 2H), 7.27-7.14 (m, 6H), 6.92-6.85 (m, 3H), 5.30(s, 2H), 4.58-4.52 (m, 1H), 3.90-3.10 (m, 4H), 1.95-1.35 (m, 4H). MS:m/z 456.3 [M+H]⁺.

The following compounds were prepared from1-(3-carboxy-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione and thecorresponding substituted piperazine using a procedure similar to thosedescribed for the synthesis of compound of Example 3.

Example 401-(3-(4-(Cyclopropylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.72 (s, 1H), 8.01 (d, J=6.6 Hz, 1H), 7.65 (t, J=7.8Hz, 1H), 7.39-7.22 (m, 5H), 5.31 (s, 2H), 3.52-3.31 (m, 8H), 2.01-1.86(m, 1H), 0.73-0.70 (m, 4H). MS: m/z 451.3 [M+H]⁺.

Example 411-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.71 (s, 1H), 8.00 (dd, J=7.8 and 1.2 Hz, 1H), 7.64(t, J=7.4 Hz, 1H), 7.43-7.21 (m, 5H), 5.30 (s, 2H), 3.58-3.10 (m, 9H),1.68-1.00 (m, 10H). MS: m/z 493.3 [M+H]⁺.

Example 421-(4-Fluoro-3-(4-(pyrazin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.71 (s, 1H), 8.29 (s, 1H), 8.08 (s, 1H), 8.00 (d,J=7.8 Hz, 1H), 7.86 (d, J=2.1 Hz, 1H), 7.65 (t, J=7.5 Hz, 1H), 7.46-7.36(m, 2H), 7.30-7.22 (m, 3H), 5.31 (s, 2H), 3.81-3.40 (m, 8H). MS: m/z461.3 [M+H]⁺.

Example 431-(3-(4-(Benzo[d]isothiazol-3-yl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.72 (s, 1H), 8.08-8.05 (m, 2H), 8.00 (dd, J=7.8 and1.2 Hz, 1H), 7.64 (t, J=7.2 Hz, 1H), 7.56 (t, J=7.7 Hz, 1H), 7.46-7.41(m, 3H), 7.31-7.19 (m, 3H), 5.31 (s, 2H), 3.87-3.81 (m, 2H), 3.49-3.31(m, 6H). MS: m/z 516.2 [M+H]⁺.

Example 441-(3-(4-(Cyclobutylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.69 (s, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.64 (t, J=8.0Hz, 1H), 7.44-7.41 (m, 1H), 7.35 (d, J=5.7 Hz, 1H), 7.28-7.21 (m, 3H),5.30 (s, 2H), 3.70-3.00 (m, 9H), 2.25-1.60 (m, 6H). MS: m/z 465.3[M+H]⁺.

Example 451-(3-(4-Benzoylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.68 (s, 1H), 7.99 (d, J=7.8 Hz, 1H), 7.70-7.10 (m,11H), 5.30 (s, 2H), 3.80-3.10 (m, 8H). MS: m/z 487.3 [M+H]⁺.

Example 461-(4-Fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.67 (s, 1H), 8.00 (d, J=7.5 Hz, 1H), 7.75 (d, J=5.1Hz, 1H), 7.62 (t, J=7.7 Hz, 1H), 7.50-7.15 (m, 6H), 7.12 (t, J=4.4 Hz,1H), 5.30 (s, 2H), 3.80-3.10 (m, 8H). MS: m/z 493.2 [M+H]⁺.

Example 471-(4-Fluoro-3-(4-(furan-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.69 (s, 1H), 8.00 (d, J=6.6 Hz, 1H), 7.83 (s, 1H),7.64 (t, J=7.1 Hz, 1H), 7.50-7.35 (m, 2H), 7.30-7.15 (m, 3H), 6.99 (d,J=3.3 Hz, 1H), 6.70-6.55 (m, 1H), 5.31 (s, 2H), 3.85-3.10 (m, 8H). MS:m/z 477.3 [M+H]⁺.

The following compounds were prepared from1-(3-carboxy-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione (prepared fromquinazoline-2,4(1H,3H)-dione and methyl 3-(bromomethyl)-4-fluorobenzoateusing a procedure similar to those used for compounds of Example 1 and2), and the corresponding substituted piperazine using a proceduresimilar to those described for the synthesis of compound of Example 3.

Example 481-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.75 (s, 1H), 8.03 (dd, J=7.8 and 1.2 Hz, 1H), 7.66(t, J=7.8 Hz, 1H), 7.38-7.35 (m, 2H), 7.26 (t, J=7.7 Hz, 1H), 7.20-7.15(m, 2H), 5.35 (s, 2H), 3.38-3.15 (m, 9H), 1.70-1.55 (m, 8H). MS: m/z479.3 [M+H]⁺.

Example 491-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.75 (s, 1H), 8.04 (d, J=7.8 Hz, 1H), 7.67 (d, J=7.4Hz, 1H), 7.50-7.10 (m, 5H), 5.37 (s, 2H), 3.70-2.90 (m, 9H), 1.80-1.00(m, 10H). MS: m/z 493.3 [M+H]⁺.

Example 501-(6-Fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.71 (s, 1H), 8.35 (d, J=4.5 Hz, 2H), 8.01 (d, J=7.6Hz, 1H), 7.67 (t, J=8.4 Hz, 1H), 7.40-7.17 (m, 5H), 6.64 (t, J=4.8 Hz,1H), 5.35 (s, 2H), 3.81-3.14 (m, 8H). MS: m/z 461.2 [M+H]⁺.

Example 511-(6-Fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.72 (s, 1H), 8.12 (d, J=3.3 Hz, 1H), 8.03 (d, J=6.6Hz, 1H), 7.70 (t, J=8.0 Hz, 1H), 7.56 (t, J=8.0 Hz, 1H), 7.42-7.18 (m,5H), 6.76 (d, J=8.4 Hz, 1H), 6.67 (dd, J=6.9 and 5.1 Hz, 1H), 5.38 (s,2H), 3.70-3.00 (m, 8H). MS: m/z 460.3 [M+H]⁺.

Example 521-(6-Fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.71 (s, 1H), 8.01 (d, J=8.1 Hz, 1H), 7.76 (d, J=4.8Hz, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.43-7.32 (m, 3H), 7.22-7.12 (m, 4H),5.35 (s, 2H), 3.80-2.90 (m, 8H). MS: m/z 493.2 [M+H]⁺.

Example 531-(3-(4-(Cyclobutylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.71 (s, 1H), 8.02 (d, J=7.8 Hz, 1H), 7.65 (t, J=8.0Hz, 1H), 7.36-7.13 (m, 5H), 5.34 (s, 2H), 3.60-2.80 (m, 9H), 2.20-1.70(m, 6H). MS: m/z 465.3 [M+H]⁺.

Example 541-(6-Fluoro-3-(4-(furan-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.71 (s, 1H), 8.01 (d, J=6.6 Hz, 1H), 7.84 (s, 1H),7.64 (t, J=7.5 Hz, 1H), 7.43-7.32 (m, 2H), 7.25-7.16 (m, 3H), 6.96 (d,J=3.0 Hz, 1H), 7.63-6.62 (m, 1H), 5.35 (s, 2H), 3.80-2.90 (m, 8H). MS:m/z 477.3 [M+H]⁺.

The following compounds were prepared from1-(3-carboxy-6-chlorobenzyl)quinazoline-2,4(1H,3H)-dione (prepared fromquinazoline-2,4(1H,3H)-dione and methyl 3-(bromomethyl)-4-chlorobenzoateusing a procedure similar to those for compounds of Example 1 and 2),and the corresponding substituted piperazine using a procedure similarto those described for the synthesis of compound of Example 3.

Example 551-(6-Chloro-3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.75 (s, 1H), 8.05 (d, J=7.8 Hz, 1H), 7.69-7.64 (m,2H), 7.37 (d, J=8.1 Hz, 1H), 7.28 (t, J=7.3 Hz, 1H), 7.08-7.02 (m, 2H),5.33 (s, 2H), 3.70-2.80 (m, 9H), 1.80-1.55 (m, 8H). MS: m/z 495.3[M+H]⁺.

Example 561-(6-Chloro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.71 (s, 1H), 8.36 (d, J=4.8 Hz, 2H), 8.03 (d, J=6.6Hz, 1H), 7.69-7.64 (m, 2H), 7.38 (d, J=6.9 Hz, 1H), 7.28 (t, J=7.5 Hz,1H), 7.09-7.04 (m, 2H), 6.65 (t, J=4.8 Hz, 1H), 5.33 (s, 2H), 3.80-3.00(m, 8H). MS: m/z 477.2 [M+H]⁺.

Example 571-(6-Chloro-3-(4-(cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.71 (s, 1H), 8.02 (d, J=7.5 Hz, 1H), 7.75-7.55 (m,2H), 7.34 (d, J=8.1 Hz, 1H), 7.25 (t, J=7.5 Hz, 1H), 7.10-6.90 (m, 2H),5.30 (s, 2H), 3.60-2.80 (m, 9H), 1.80-1.00 (m, 10H). MS: m/z 509.3[M+H]⁺.

Example 581-(6-Chloro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.73 (s, 1H), 8.11 (d, J=3.6 Hz, 1H), 8.03 (d, J=7.8Hz, 1H), 7.80-7.60 (m, 2H), 7.55 (t, J=6.9 Hz, 1H), 7.39 (d, J=6.6 Hz,1H), 7.30 (t, J=7.5 Hz, 1H), 7.15-7.00 (m, 2H), 6.72 (d, J=8.4 Hz, 1H),6.66 (dd, J=6.8 and 5.0 Hz, 1H), 5.34 (s, 2H), 3.70-3.00 (m, 8H). MS:m/z 476.2 [M+H]⁺.

The following compounds were prepared from1-(3-carboxyl-2-chlorobenzyl)quinazoline-2,4(1H,3H)-dione (prepared fromquinazoline-2,4(1H,3H)-dione and methyl 3-(bromomethyl)-2-chlorobenzoateusing a procedure similar to those used for compounds of Example 1 and2), and the corresponding substituted piperazine using a proceduresimilar to those described for the synthesis of compound of Example 3.

Example 591-(2-Chloro-3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.78 (s, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.67 (t, J=7.5Hz, 1H), 7.45-7.20 (m, 3H), 7.15-6.95 (m, 2H), 5.50-5.15 (m, 2H),3.80-3.10 (m, 8H), 3.04-2.94 (m, 1H), 1.90-1.35 (m, 8H). MS: m/z 495.3[M+H]⁺.

Example 601-(2-Chloro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.88 (s, 1H), 8.49 (d, J=4.8 Hz, 2H), 8.16 (d, J=7.8Hz, 1H), 7.77 (t, J=7.8 Hz, 1H), 7.50-7.30 (m, 3H), 7.25-7.05 (m, 2H),6.78 (t, J=7.7 Hz, 1H), 5.60-5.30 (m, 2H), 4.10-3.70 (m, 8H). MS: m/z477.2 [M+H]⁺.

The following compounds were prepared from1-(3-carboxy-2-fluorobenzyl)quinazoline-2,4(1H,3H)-dione (prepared fromquinazoline-2,4(1H,3H)-dione and methyl 3-(bromomethyl)-2-fluorobenzoateusing a procedure similar to those used for compounds of Example 1 and2), and the corresponding substituted piperazine using a proceduresimilar to those described for the synthesis compound of Example 3.

Example 611-(2-Fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.71 (s, 1H), 8.37 (d, J=4.8 Hz, 2H), 8.03 (d, J=6.6Hz, 1H), 7.66 (t, J=7.1 Hz, 1H), 7.45-7.05 (m, 5H), 6.66 (t, J=4.7 Hz,1H), 5.35 (s, 2H), 3.90-3.60 (m, 8H). MS: m/z 461.3 [M+H]⁺.

Example 621-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)-2-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.74 (s, 1H), 8.03 (d, J=7.5 Hz, 1H), 7.66 (t, J=7.7Hz, 1H), 7.40-7.10 (m, 5H), 5.34 (s, 2H), 3.80-3.20 (m, 8H), 3.10-2.80(m, 1H), 1.90-1.40 (m, 8H). MS: m/z 479.3 [M+H]⁺.

The following compounds were prepared from1-(3-carboxy-5-fluorobenzyl)quinazoline-2,4(1H,3H)-dione (prepared fromquinazoline-2,4(1H,3H)-dione and methyl 3-(bromomethyl)-5-fluorobenzoateusing a procedure similar to those used for compounds of Example 1 and2), and the corresponding substituted piperazine using a proceduresimilar to those described for the synthesis compound of Example 3.

Example 631-(5-Fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.68 (s, 1H), 8.36 (d, J=4.8 Hz, 2H), 8.00 (d, J=7.8Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.30-7.15 (m, 5H), 6.64 (t, J=4.8 Hz,1H), 5.34 (s, 2H), 3.80-3.50 (m, 8H). MS: m/z 461.3 [M+H]⁺.

Example 641-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)-5-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.69 (s, 1H), 8.00 (d, J=9.0 Hz, 1H), 7.64 (t, J=7.1Hz, 1H), 7.31-7.15 (m, 5H), 5.34 (s, 2H), 3.70-3.10 (m, 8H), 2.94-2.86(m, 1H), 1.80-1.40 (m, 8H). MS: m/z 479.3 [M+H]⁺.

The following compounds were prepared from1-(3-carboxy-4-chlorobenzyl)quinazoline-2,4(1H,3H)-dione (prepared fromquinazoline-2,4(1H,3H)-dione and methyl 5-(bromomethyl)-2-chlorobenzoateusing a procedure similar to those used for compounds of Example 1 and2), and the corresponding substituted piperazine using a proceduresimilar to those described for the synthesis compound of Example 3.

Example 651-(4-Chloro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (CD₃OD): 8.38 (d, J=4.6 Hz, 2H), 8.16 (d, J=9.0 Hz, 1H), 7.69 (t,J=8.7 Hz, 1H), 7.54-7.29 (m, 5H), 6.67 (t, J=4.6 Hz, 1H), 5.51-5.39 (m,2H), 3.98-3.57 (m, 8H). MS: m/z 477.2 [M+H]⁺.

Example 661-(4-Chloro-3-(4-(cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.60 (s, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.53 (t, J=7.5Hz, 1H), 7.39 (d, J=9.0 Hz, 1H), 7.28-7.26 (m, 2H), 7.16-7.07 (m, 2H),5.31-5.13 (m, 2H), 3.48-2.90 (m, 9H), 1.59-1.09 (m, 10H). MS: m/z 509.3[M+H]⁺.

The following compounds were prepared from1-((2-carboxy-furan-5-yl)methyl)quinazoline-2,4(1H,3H)-dione (preparedfrom quinazoline-2,4(1H,3H)-dione and ethyl5-(chloromethyl)furan-2-carboxylate using a procedure similar to thosedescribed for the synthesis of compounds of Example 1 and 2), and thecorresponding substituted piperazine using a procedure similar to thosedescribed for the synthesis of compound of Example 3.

Example 671-((2-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)furan-5-yl)methyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆) 11.75 (s, 1H), 8.01 (d, J=7.5 Hz, 1H), 7.74 (t, J=7.5Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.28 (t, J=7.5 Hz, 1H), 6.96 (d, J=3.3Hz, 1H), 6.59 (d, J=3.3 Hz, 1H), 5.36 (s, 2H), 3.61-3.14 (m, 9H),1.73-1.54 (m, 8H). MS: m/z 451.3 [M+1]⁺.

Example 681-((2-(4-(Benzo[d]isothiazol-3-yl)piperazine-1-carbonyl)furan-5-yl)methyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆) 11.74 (s, 1H), 8.10-8.08 (m, 2H), 8.02 (d, J=7.8 Hz,1H), 7.76 (t, J=4.5 Hz, 1H), 7.61-7.57 (m, 2H), 7.48 (t, J=7.5 Hz, 1H),7.30-7.25 (m, 1H), 7.00 (d, J=3.3 Hz, 1H), 6.60 (d, J=3.3 Hz, 1H), 5.39(s, 2H), 3.85-3.78 (m, 4H), 3.49-3.40 (m, 4H). MS: m/z 488.2 [M+1]⁺.

The following compounds were prepared from1-((2-carboxylpyridin-6-yl)methyl)quinazoline-2,4(1H,3H)-dione (preparedfrom quinazoline-2,4(1H,3H)-dione and methyl6-(bromomethyl)pyridine-2-carboxylate using a procedure similar to thosedescribed for the synthesis of compounds of Example 1 and 2), and thecorresponding substituted piperazine using a procedure similar to thosedescribed for the synthesis of compound of Example 3.

Example 691-((2-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)pyridin-6-yl)methyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (CD₃OD): 8.16 (d, J=6.3 Hz, 1H), 7.98-7.96 (m, 1H), 7.64-7.59 (m,3H), 7.32-7.26 (m, 2H), 5.57 (s, 2H), 3.70-3.58 (m, 4H), 3.31-2.92 (m,5H), 1.84-1.70 (m, 8H). MS: m/z 462.3 [M+H]⁺.

Example 701-((2-(4-(Pyridin-2-yl)piperazine-1-carbonyl)pyridin-6-yl)methyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (CD₃OD): 8.15-8.12 (m, 2H), 7.96 (t, J=7.5 Hz, 1H), 7.67-7.58 (m,4H), 7.30-7.25 (m, 2H), 6.80-6.71 (m, 2H), 5.57 (s, 2H), 3.81-3.78 (m,2H), 3.59-3.55 (m, 2H), 3.44-3.41 (m, 2H), 3.23-3.19 (m, 2H). MS: m/z443.3 [M+H]⁺.

Example 711-((2-(4-(Pyrimidin-2-yl)piperazine-1-carbonyl)pyridin-6-yl)methyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (CD₃OD): 8.36 (d, J=4.8 Hz, 2H), 8.14 (d, J=6.9 Hz, 1H), 7.96 (t,J=7.5 Hz, 1H), 7.65-7.58 (m, 3H), 7.31-7.28 (m, 2H), 6.64 (t, J=4.8 Hz,1H), 5.57 (s, 2H), 3.85-3.82 (m, 2H), 3.78-3.73 (m, 2H), 3.57-3.53 (m,2H), 3.39-3.35 (m, 2H). MS: m/z 444.3 [M+H]⁺.

The following compounds were prepared from1-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione and the correspondingsubstituted piperazine using a procedure similar to those described forthe synthesis of compound of Example 3.

Example 721-(3-(4-(Thiazol-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.72 (s, 1H), 8.03 (d, J=7.3 Hz, 1H), 7.66 (t, J=7.7Hz, 1H), 7.46-7.23 (m, 6H), 7.18 (d, J=3.6 Hz, 1H), 6.88 (d, J=3.6 Hz,1H), 5.37 (s, 2H), 3.80-3.40 (m, 8H). MS: m/z 448.3 [M+H]⁺.

Example 731-(3-(4-(Cyclohexylmethyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.75 (s, 1H), 8.02 (dd, J=8.0 and 1.4 Hz, 1H),7.67-7.62 (m, 1H), 7.41-7.39 (m, 2H), 7.27-7.23 (m, 4H), 5.35 (s, 2H),3.54-3.15 (m, 4H), 2.32-2.03 (m, 6H), 1.73-1.44 (m, 5H), 1.23-1.06 (m,6H). MS: m/z 461.3 [M+1]⁺.

Example 741-(3-(4-(Cyclopentylmethyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.73 (s, 1H), 8.03 (d, J=7.5 Hz, 1H), 7.65 (d, J=7.5Hz, 1H), 7.42-7.23 (m, 6H), 5.36 (s, 2H), 3.54-2.87 (m, 6H), 2.25-2.20(m, 4H), 1.80-1.24 (m, 9H). MS: m/z 447.3 [M+1]⁺.

Example 751-(3-(4-(Cyclohexylsulfonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.69 (s, 1H), 8.01 (dd, J=8.0 and 1.4 Hz, 1H),7.64-7.60 (m, 1H), 7.42-7.38 (m, 2H), 7.29-7.16 (m, 4H), 5.35 (s, 2H),3.56-3.52 (m, 2H), 3.20-3.05 (m, 6H), 1.96-1.93 (m, 1H), 1.80-1.76 (m,2H), 1.62-1.58 (m, 2H), 1.27-1.22 (m, 6H). MS: m/z 511.3 [M+1]⁺.

Example 76 7-Fluoroquinazoline-2,4(1H,3H)-dione

To a mixture of 2-amino-4-fluorobenzoic acid (4.0 g, 26 mmol) andpotassium cyanate (3.5 g, 43 mmol) in water (200 mL) was added aceticacid (3 mL, 45 mmol) and the mixture was stirred at room temperature forabout 5 h. To the mixture was added NaOH (15 g, 375 mmol) and it wasstirred for another 1 h. The mixture was filtered and the solid wasmixed in hot water, and it was adjusted to pH=5˜6 by addition of aceticacid. The mixture was filtered and washed with water, dried to give thetitle compound (3.0 g, 65% yield) as gray solid. MS: m/z 181.1 [M+H]⁺

The following compounds were prepared from1-(3-carboxybenzyl)-7-fluoroquinazoline-2,4(1H,3H)-dione (prepared from7-fluoroquinazoline-2,4(1H,3H)-dione and methyl 3-(bromomethyl)benzoateusing a procedure similar to those for compounds of Example 1 and 2),and the corresponding substituted piperazine using a procedure similarto those described for the synthesis of compound of Example 3.

Example 771-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)-7-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.81 (s, 1H), 8.08 (t, J=7.6 Hz, 1H), 7.44-7.31 (m,4H), 7.18-7.12 (m, 2H), 5.34 (s, 2H), 3.70-2.80 (m, 9H), 1.80-1.55 (m,8H). MS: m/z 479.3 [M+H]⁺.

Example 787-Fluoro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.79 (s, 1H), 8.37 (d, J=4.8 Hz, 2H), 8.05 (t, J=7.6Hz, 1H), 7.45-7.31 (m, 4H), 7.17-7.07 (m, 2H), 6.65 (t, J=4.8 Hz, 1H),5.33 (s, 2H), 3.78-3.55 (m, 8H). MS: m/z 461.3 [M+H]⁺.

The following compounds were prepared from1-(3-carboxybenzyl)-7-methylquinazoline-2,4(1H,3H)-dione (prepared from7-methylquinazoline-2,4(1H,3H)-dioneand methyl 3-(bromomethyl)benzoateusing a procedure similar to those for compounds of Example 1 and 2),and the corresponding substituted piperazine using a procedure similarto those described for the synthesis of compound of Example 3.

Example 791-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)-7-methylquinazoline-2,4(1H,3H)-dione

¹H NMR (CD₃OD): 8.04 (d, J=8.1 Hz, 1H), 7.51-7.49 (m, 2H), 7.40-7.38 (m,2H), 7.15-7.11 (m, 2H), 5.45 (s, 2H), 3.75-3.50 (m, 8H), 3.12-3.09 (m,1H), 2.39 (s, 3H), 1.88-1.64 (m, 8H). MS: m/z 475.3 [M+H]⁺.

Example 807-Methyl-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (CD₃OD): 8.38-8.36 (m, 2H), 8.04 (d, J=7.8 Hz, 1H), 7.52-7.50 (m,2H), 7.42-7.40 (m, 2H), 7.16-7.13 (m, 2H), 6.66 (t, J=4.8 Hz, 1H), 5.46(s, 2H), 3.92-3.56 (m, 8H), 2.40 (s, 3H). MS: m/z 457.3 [M+H]⁺.

The following compounds were prepared from1-(3-carboxybenzyl)-6-methylquinazoline-2,4(1H,3H)-dione (prepared from6-methylquinazoline-2,4(1H,3H)-dione and methyl 3-(bromomethyl)benzoateusing a procedure similar to those for compounds of Example 1 and 2),and the corresponding substituted piperazine using a procedure similarto those described for the synthesis of compound of Example 3.

Example 816-Methyl-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (CD₃OD): 8.34 (d, J=4.8 Hz, 2H), 7.94 (s, 1H), 7.49-7.47 (m, 3H),7.39-7.34 (m, 2H), 7.18 (d, J=8.4 Hz, 1H), 6.64 (t, J=4.8 Hz, 1H), 5.44(s, 2H), 3.89-3.39 (m, 8H), 2.39 (s, 3H). MS: m/z 457.3 [M+H]⁺.

Example 821-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)-6-methylquinazoline-2,4(1H,3H)-dione

¹H NMR (CD₃OD): 7.95 (s, 1H), 7.49-7.47 (m, 3H), 7.38-7.35 (m, 2H), 7.18(d, J=8.7 Hz, 1H), 5.43 (s, 2H), 3.71-3.69 (m, 4H), 3.49-3.47 (m, 4H),3.09-3.08 (m, 1H), 2.39 (s, 3H), 1.88-1.63 (m, 8H). MS: m/z 475.3[M+H]⁺.

The following compounds were prepared from1-(3-carboxy-4-fluorobenzyl)-6-methylquinazoline-2,4(1H,3H)-dione(prepared from 6-methylquinazoline-2,4(1H,3H)-dione and methyl5-(bromomethyl)-2-fluorobenzoate using a procedure similar to those forcompounds of Example 1 and 2), and the corresponding substitutedpiperazine using a procedure similar to those described for thesynthesis of compound of Example 3.

Example 831-(4-Fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-6-methylquinazoline-2,4(1H,3H)-dione

¹H NMR (CD₃OD): 8.37 (d, J=4.8 Hz, 2H), 7.96 (s, 1H), 7.54-7.51 (m, 2H),7.40 (dd, J=6.3 and 2.1 Hz, 1H), 7.28-7.21 (m, 2H), 6.66 (t, J=4.8 Hz,1H), 5.41 (s, 2H), 3.93-3.56 (m, 8H), 2.41 (s, 3H). MS: m/z 475.3[M+H]⁺.

Example 841-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-6-methylquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.54 (s, 1H), 7.71 (s, 1H), 7.38-7.24 (m, 3H), 7.16(t, J=9.0 Hz, 1H), 7.04 (d, J=8.7 Hz, 1H), 5.19 (s, 2H), 3.45-2.99 (m,9H), 2.22 (s, 3H), 1.59-1.49 (m, 5H), 1.22-1.13 (m, 5H). MS: m/z 507.3[M+H]⁺.

Example 851-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-6-methylquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.63 (s, 1H), 7.80 (s, 1H), 7.46-7.22 (m, 4H), 7.12(d, J=8.4 Hz, 1H), 5.27 (s, 2H), 3.55-2.97 (m, 8H), 2.99-2.84 (m, 1H),2.30 (s, 3H), 1.73-1.49 (m, 8H). MS: m/z 493.3 [M+H]⁺.

The following compounds were prepared from6-bromo-1-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione (prepared from6-bromoquinazoline-2,4(1H,3H)-dione and methyl 3-(bromomethyl)benzoateusing a procedure similar to those for compounds of Example 1 and 2),and the corresponding substituted piperazine using a procedure similarto those described for the synthesis of compound of Example 3.

Example 866-Bromo-1-(3-(4-(cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.86 (s, 1H), 8.05 (d, J=2.4 Hz, 1H), 7.79 (dd, J=9.0and 2.4 Hz, 1H), 7.40-7.38 (m, 2H), 7.30-7.27 (m, 2H), 7.16 (d, J=9.0Hz, 1H), 5.32 (s, 2H), 3.80-3.11 (m, 9H), 1.68-1.59 (m, 5H), 1.32-1.19(m, 5H). MS: m/z 553.3 [M+H]⁺.

Example 876-Bromo-1-(3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.86 (s, 1H), 8.04 (d, J=2.4 Hz, 1H), 7.78 (dd, J=9.0and 2.4 Hz, 1H), 7.41-7.38 (m, 2H), 7.29-7.27 (m, 2H), 7.15 (d, J=8.7Hz, 1H), 5.32 (s, 2H), 3.57-2.90 (m, 9H), 1.71-1.51 (m, 8H). MS: m/z539.2 [M+H]⁺.

Example 886-Bromo-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (CD₃OD): 8.38 (d, J=4.8 Hz, 2H), 8.25-8.24 (m, 1H), 7.78 (dd,J=8.9 and 2.3 Hz, 1H), 7.52-7.50 (m, 2H), 7.42-7.41 (m, 2H), 7.25 (d,J=9.3 Hz, 1H), 6.66 (t, J=4.6 Hz, 1H), 5.45 (s, 2H), 3.93-3.40 (m, 8H).MS: m/z 521.2 [M+H]⁺.

Example 89 6-Nitroquinazoline-2,4(1H,3H)-dione

A mixture of 2-amino-5-nitrobenzoic acid (0.588 g, 3.23 mmol) and urea(1.164 g, 19.38 mmol) was heated at 200° C. under N₂ for 1 h. Themixture was cooled to room temperature and 4 M NaOH was added untilpH=14. It was acidified to pH=5.0 via addition of AcOH. The mixture wasfiltered and the yellow solid was dried to give the title compound (0.49g, 72.8%) as a yellow solid. MS: m/z 208.1 [M+1]+.

The following compounds were prepared from1-(3-carboxybenzyl)-6-nitroquinazoline-2,4(1H,3H)-dione (prepared from6-nitroquinazoline-2,4(1H,3H)-dione and methyl 3-(bromomethyl)benzoateusing a procedure similar to those for compounds of Example 1 and 2),and the corresponding substituted piperazine using a procedure similarto those described for the synthesis of compound of Example 3.

Example 901-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)-6-nitroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 12.22 (s, 1H), 8.77 (d, J=2.4 Hz, 1H), 8.51 (dd, J=9.3and 2.4 Hz, 1H), 7.52-7.46 (m, 3H), 7.43-7.39 (m, 2H), 5.50 (s, 2H),3.58-2.96 (m, 9H), 1.68-1.31 (m, 8H). MS: m/z 506.3 [M+H]⁺.

Example 916-Nitro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 12.10 (s, 1H), 8.66 (d, J=2.7 Hz, 1H), 8.44 (d, J=9.3Hz, 1H), 8.33 (d, J=4.5 Hz, 2H), 7.45-7.39 (m, 3H), 7.34-7.32 (m, 2H),6.65 (t, J=4.6 Hz, 1H), 5.42 (s, 2H), 3.77-3.46 (m, 8H). MS: m/z 488.3[M+H]⁺.

Example 921-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)-6-nitroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 12.21 (s, 1H), 8.77 (d, J=2.7 Hz, 1H), 8.51 (dd, J=9.2and 2.6 Hz, 1H), 7.52-7.50 (m, 3H), 7.44-7.39 (m, 2H), 5.50 (s, 2H),3.68-3.24 (m, 9H), 1.78-1.68 (m, 5H), 1.45-1.23 (m, 5H). MS: m/z 520.3[M+H]⁺.

The following compounds were prepared from1-(4-carboxybenzyl)quinazoline-2,4(1H,3H)-dione (prepared fromquinazoline-2,4(1H,3H)-dione and methyl 4-(bromomethyl)benzoate using aprocedure similar to those used for Examples 1 and 2), and thecorresponding substituted piperazine using a procedure similar to thosedescribed for the synthesis of compound of Example 3.

Example 931-(4-(4-Benzoylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (CD₃OD): 8.17 (d, J=7.5 Hz, 1H), 7.68-7.63 (m, 1H), 7.53-7.41 (m,9H), 7.30-7.27 (m, 2H), 5.46 (s, 2H), 3.76-3.40 (m, 8H). MS: m/z 469.2[M+H]⁺.

Example 941-(4-(4-(Pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (CD₃OD): 8.15 (d, J=8.1 Hz, 1H), 8.11 (d, J=5.1 Hz, 1H),7.67-7.59 (m, 2H), 7.49-7.43 (m, 4H), 7.32-7.27 (m, 2H), 6.86 (d, J=8.4Hz, 1H), 6.72 (t, J=6.0 Hz, 1H), 5.46 (s, 2H), 3.85-3.42 (m, 8H). MS:m/z 442.2 [M+H]⁺.

Example 951-(4-(4-(4-Methoxybenzoyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (CD₃OD): 8.15 (d, J=7.5 Hz, 1H), 7.64 (t, J=7.5 Hz, 1H),7.43-7.41 (m, 6H), 7.31-7.26 (m, 2H), 7.02-6.99 (m, 2H), 5.45 (s, 2H),3.84 (s, 3H), 3.80-3.40 (m, 8H). MS: m/z 499.2 [M+H]⁺.

Example 961-(4-(4-(4-Fluorobenzoyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (CD₃OD): 8.15 (d, J=6.9 Hz, 1H), 7.66-7.61 (m, 1H), 7.59-7.44 (m,6H), 7.28-7.21 (m, 4H), 5.45 (s, 2H), 3.65-3.40 (m, 8H). MS: m/z 487.2[M+H]⁺.

Example 971-(4-(4-(Pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (CD₃OD): 8.35 (d, J=4.8 Hz, 2H), 8.16 (dd, J=8.0 and 1.1 Hz, 1H),7.65 (t, J=6.9 Hz, 1H), 7.49-7.41 (m, 4H), 7.32-7.28 (m, 2H), 6.64 (t,J=4.8 Hz, 1H), 5.46 (s, 2H), 3.80-3.40 (m, 8H). MS: m/z 443.3 [M+H]⁺.

Example 981-(4-(4-(4-Bromobenzoyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (CD₃OD): 8.16 (d, J=7.8 Hz, 1H), 7.88-7.63 (m, 3H), 7.49-7.39 (m,6H), 7.32-7.27 (m, 2H), 5.45 (s, 2H), 3.90-3.42 (m, 8H). MS: 547.2[M+H]⁺.

Example 991-(4-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (CD₃OD): 8.15 (dd, J=8.1 and 1.5 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H),7.49-7.42 (m, 4H), 7.31-7.26 (m, 2H), 5.45 (s, 2H), 3.83-3.39 (m, 8H),3.09-3.00 (m, 1H), 2.02-1.51 (m, 8H). MS: 461.3 [M+H]⁺.

The following compounds were prepared from5-chloro-1-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione (prepared from5-chloroquinazoline-2,4(1H,3H)-dione and methyl 3-(bromomethyl)benzoateusing a procedure similar to those used for Examples 1 and 2), and thecorresponding substituted piperazine using a procedure similar to thosedescribed for the synthesis of compound of Example 3.

Example 1005-Chloro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (CD₃OD): 8.38 (d, J=4.8 Hz, 2H), 7.60-7.50 (m, 3H), 7.45-7.39 (m,2H), 7.35-7.20 (m, 2H), 7.26 (d, J=8.4 Hz, 1H), 6.66 (t, J=4.7 Hz, 1H),5.48 (s, 2H), 4.00-3.40 (m, 8H). MS: m/z 477.2 [M+H]⁺.

Example 1015-Chloro-1-(3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (CD₃OD): 7.60-7.49 (m, 3H), 7.40-7.35 (m, 2H), 7.31 (d, J=9.0 Hz,1H), 7.23 (d, J=9.0 Hz, 1H), 5.46 (s, 2H), 3.85-2.90 (m, 9H), 2.00-1.55(m, 8H). MS: m/z 495.3 [M+H]⁺.

Example 1025-Chloro-1-(3-(4-(cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.68 (s, 1H), 7.53 (t, J=8.3 Hz, 1H), 7.45-7.39 (m,2H), 7.30-7.20 (m, 3H), 7.15 (d, J=8.7 Hz, 1H), 5.34 (s, 2H), 3.70-3.00(m, 9H), 1.80-1.00 (m, 10H). MS: m/z 509.3 [M+H]⁺.

The following compounds were prepared from5-chloro-1-(3-carboxy-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione(prepared from 5-chloroquinazoline-2,4(1H,3H)-dione and methyl5-(bromomethyl)-2-fluorobenzoate using a procedure similar to those usedfor Examples 1 and 2), and the corresponding substituted piperazineusing a procedure similar to those described for the synthesis ofcompound of Example 3.

Example 1035-Chloro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.69 (s, 1H), 8.39 (d, J=4.5 Hz, 2H), 7.50 (t, J=7.8Hz, 1H), 7.47-7.39 (m, 2H), 7.32-7.25 (m, 2H), 7.20 (d, J=9.0 Hz, 1H),6.67 (t, J=4.5 Hz, 1H), 5.32 (s, 2H), 3.81-3.33 (m, 8H). MS: m/z 495.2[M+H]⁺.

Example 1045-Chloro-1-(3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.69 (s, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.47-7.42 (m,1H), 7.38 (d, J=6.0 Hz, 1H), 7.31-7.25 (m, 2H), 7.18-7.14 (m, 1H), 5.31(s, 2H), 3.70-3.00 (m, 9H), 1.85-1.40 (m, 8H). MS: m/z 513.3 [M+H]⁺.

Example 1055-Chloro-1-(3-(4-(cyclohexylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.67 (s, 1H), 7.53 (t, J=8.3 Hz, 1H), 7.45-7.41 (m,1H), 7.35 (dd, J=6.2 and 2.0 Hz, 1H), 7.31-7.20 (m, 2H), 7.15 (s, 1H),5.29 (s, 2H), 3.70-3.00 (m, 9H), 1.80-1.00 (m, 10H). MS: m/z 527.3[M+H]⁺.

Example 1065-Chloro-1-(4-fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.66 (s, 1H), 8.11 (d, J=1.8 Hz, 1H), 7.57-7.52 (m,2H), 7.45-7.37 (m, 2H), 7.31-7.20 (m, 2H), 7.17 (d, J=8.7 Hz, 1H), 6.81(d, J=8.7 Hz, 1H), 6.56 (t, J=6.0 Hz, 1H), 5.30 (s, 2H), 3.80-3.10 (m,8H). MS: m/z 494.2 [M+H]⁺.

Example 1075-Chloro-1-(4-fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.68 (s, 1H), 7.76 (dd, J=5.0 and 1.1 Hz, 1H), 7.46(t, J=8.4 Hz, 1H), 7.49-7.36 (m, 3H), 7.30-7.19 (m, 2H), 7.15-7.05 (m,2H), 5.30 (s, 2H), 3.80-3.15 (m, 8H). MS: m/z 527.2 [M+H]⁺.

The following compounds were prepared from5-chloro-1-(6-fluoro-3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione(prepared from 5-chloroquinazoline-2,4(1H,3H)-dione and methyl3-(bromomethyl)-4-fluorobenzoate using a procedure similar to those usedfor Examples 1 and 2), and the corresponding substituted piperazineusing a procedure similar to those described for the synthesis ofcompound of Example 3.

Example 1085-Chloro-1-(3-(4-(cyclohexylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.70 (s, 1H), 7.55 (t, J=8.7 Hz, 1H), 7.45-7.34 (m,2H), 7.27 (d, J=7.5 Hz, 1H), 7.17 (d, J=6.9 Hz, 1H), 7.13 (d, J=7.8 Hz,1H), 5.33 (s, 2H), 3.80-3.00 (m, 9H), 1.80-1.10 (m, 10H). MS: m/z 527.3[M+H]⁺.

Example 1095-Chloro-1-(3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.71 (s, 1H), 7.57 (t, J=8.3 Hz, 1H), 7.45-7.25 (m,3H), 7.20 (d, J=7.5 Hz, 1H), 7.14 (d, J=8.7 Hz, 1H), 5.35 (s, 2H),3.70-2.80 (m, 9H), 1.85-1.40 (m, 8H). MS: m/z 513.3 [M+H]⁺.

Example 1105-Chloro-1-(6-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.68 (s, 1H), 8.35 (d, J=4.5 Hz, 2H), 7.56 (t, J=8.4Hz, 1H), 7.45-7.27 (m, 3H), 7.22 (d, J=6.6 Hz, 1H), 7.15 (d, J=8.7 Hz,1H), 6.64 (t, J=4.5 Hz, 1H), 5.34 (s, 2H), 3.80-3.10 (m, 8H). MS: m/z495.3 [M+H]⁺.

The following compounds were prepared from6-chloro-1-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione (prepared from6-chloroquinazoline-2,4(1H,3H)-dione and methyl 3-(bromomethyl)benzoateusing a procedure similar to those used for Examples 1 and 2), and thecorresponding substituted piperazine using a procedure similar to thosedescribed for the synthesis of compound of Example 3.

Example 1116-Chloro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (CD₃OD): 8.37 (d, J=4.8 Hz, 2H), 8.09 (d, J=2.7 Hz, 1H), 7.64(dd, J=9.2 and 2.6 Hz, 1H), 7.55-7.45 (m, 2H), 7.45-7.35 (m, 2H), 7.32(d, J=9.0 Hz, 1H), 6.66 (t, J=4.7 Hz, 1H), 5.45 (s, 2H), 4.00-3.33 (m,8H). MS: m/z 477.2 [M+H]⁺.

Example 1126-Chloro-1-(3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.87 (s, 1H), 7.94 (d, J=2.7 Hz, 1H), 7.70 (dd, J=9.0and 2.7 Hz, 1H), 7.46-7.38 (m, 2H), 7.31-7.23 (m, 3H), 5.35 (s, 2H),3.70-2.80 (m, 9H), 1.90-1.40 (m, 8H). MS: m/z 495.2 [M+H]⁺.

Example 1136-Chloro-1-(3-(4-(cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.88 (s, 1H), 7.94 (d, J=2.4 Hz, 1H), 7.74 (dd, J=9.0and 2.4 Hz, 1H), 7.46-7.37 (m, 2H), 7.32-7.23 (m, 3H), 5.35 (s, 2H),3.80-3.10 (m, 9H), 1.80-1.10 (m, 10H). MS: m/z 509.3 [M+H]⁺.

Example 1146-Chloro-1-(3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.95 (s, 1H), 8.21-8.20 (m, 1H), 8.02 (s, 1H),7.82-7.78 (m, 1H), 7.66-7.60 (m, 1H), 7.49-7.42 (m, 5H), 6.89 (d, J=3.0Hz, 1H), 6.75 (t, J=6.0 Hz, 1H), 5.44 (s, 2H), 3.85-3.29 (m, 8H). MS:m/z 476.3 [M+H]⁺.

Example 1156-Chloro-1-(3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.87 (s, 1H), 7.92 (d, J=2.7 Hz, 1H), 7.76 (d, J=4.8Hz, 1H), 7.67 (dd, J=8.9 and 2.6 Hz, 1H), 7.50-7.35 (m, 3H), 7.32-7.29(m, 2H), 7.23 (d, J=9.0 Hz, 1H), 7.12 (dd, J=4.8 and 3.6 Hz, 1H), 5.33(s, 2H), 3.79-3.45 (m, 8H). MS: m/z 509.2 [M+H]⁺.

Example 1166-Chloro-1-(3-(4-(cyclobutylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.87 (s, 1H), 7.93 (d, J=2.4 Hz, 1H), 7.68 (dd, J=9.0and 2.4 Hz, 1H), 7.43-7.35 (m, 2H), 7.31-7.22 (m, 3H), 5.33 (s, 2H),3.60-3.00 (m, 9H), 2.20-1.60 (m, 6H). MS: m/z 481.3 [M+H]⁺.

The following compounds were prepared from6-chloro-1-(3-carboxy-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione(prepared from 6-chloroquinazoline-2,4(1H,3H)-dione and methyl5-(bromomethyl)-2-fluorobenzoate using a procedure similar to those usedfor Examples 1 and 2), and the corresponding substituted piperazineusing a procedure similar to those described for the synthesis ofcompound of Example 3.

Example 1176-Chloro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.84 (s, 1H), 8.37 (d, J=4.8 Hz, 2H), 7.92 (s, 1H),7.69 (dd, J=8.9 and 2.6 Hz, 1H), 7.47-7.36 (m, 2H), 7.30-7.24 (m, 2H),6.65 (t, J=4.8 Hz, 1H), 5.30 (s, 2H), 3.78-3.21 (m, 8H). MS: m/z 495.2[M+H]⁺.

Example 1186-Chloro-1-(3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.85 (s, 1H), 7.92 (d, J=2.4 Hz, 1H), 7.68 (dd, J=9.0and 2.4 Hz, 1H), 7.44-7.41 (m, 1H), 7.36-7.34 (m, 1H), 7.30-7.15 (m,2H), 5.29 (s, 2H), 3.70-2.80 (m, 9H), 1.80-1.40 (m, 8H). MS: m/z 513.3[M+H]⁺.

Example 1196-Chloro-1-(3-(4-(cyclohexylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.85 (s, 1H), 7.92 (d, J=2.1 Hz, 1H), 7.68 (dd, J=8.7and 2.4 Hz, 1H), 7.45-7.39 (m, 1H), 7.35 (d, J=5.4 Hz, 1H), 7.31-7.15(m, 2H), 5.29 (s, 2H), 3.70-3.00 (m, 9H), 1.80-1.10 (m, 10H). MS: m/z527.3 [M+H]⁺.

Example 1206-Chloro-1-(4-fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 8.10 (d, J=3.6 Hz, 1H), 7.92 (s, 1H), 7.69 (d, J=9.0Hz, 1H), 7.54 (t, J=9.0 Hz, 1H), 7.45-7.36 (m, 2H), 7.30-7.23 (m, 2H),6.81 (d, J=7.8 Hz, 1H), 6.66 (t, J=6.3 Hz, 1H), 5.30 (s, 2H), 3.68-3.21(m, 8H). MS: m/z 494.2 [M+H]⁺.

Example 1216-Chloro-1-(4-fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.86 (s, 1H), 7.92 (s, J=2.4 Hz, 1H), 7.76 (d, J=4.2Hz, 1H), 7.68 (dd, J=9.0 and 2.4 Hz, 1H), 7.46-7.36 (m, 3H), 7.30-7.22(m, 2H), 7.12 (dd, J=5.0 and 3.8 Hz, 1H), 5.30 (s, 2H), 3.68-3.21 (m,8H). MS: m/z 527.2 [M+H]⁺.

Example 1226-Chloro-1-(3-(4-(cyclopropylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.85 (s, 1H), 7.94 (s, 1H), 7.70 (dd, J=8.4 and 2.1Hz, 1H), 7.47-7.23 (m, 4H), 5.31 (s, 2H), 3.59-3.09 (m, 8H), 2.01-1.96(m, 1H), 0.77-0.69 (m, 4H). MS: m/z 485.3 [M+H]⁺.

The following compounds were prepared from6-chloro-1-(6-fluoro-3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione(prepared from 6-chloroquinazoline-2,4(1H,3H)-dione and methyl3-(bromomethyl)-4-fluorobenzoate using a procedure similar to those usedfor Examples 1 and 2), and the corresponding substituted piperazineusing a procedure similar to those described for the synthesis ofcompound of Example 3.

Example 1236-Chloro-1-(6-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.88 (s, 1H), 8.36 (d, J=4.5 Hz, 2H), 7.93 (d, J=2.4Hz, 1H), 7.73 (dd, J=9.0 and 2.4 Hz, 1H), 7.36-7.20 (m, 4H), 6.65 (t,J=4.8 Hz, 1H), 5.37 (s, 2H), 3.78-3.21 (m, 8H). MS: m/z 495.2 [M+H]⁺.

Example 1246-Chloro-1-(3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.87 (s, 1H), 7.94 (d, J=2.4 Hz, 1H), 7.71 (dd, J=9.2and 2.3 Hz, 1H), 7.42-7.32 (m, 2H), 7.23-7.17 (m, 2H), 5.34 (s, 2H),3.59-3.09 (m, 9H), 1.71-1.56 (m, 8H). MS: m/z 513.3 [M+H]⁺.

Example 1256-Chloro-1-(3-(4-(cyclohexylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.87 (s, 1H), 7.93 (d, J=2.4 Hz, 1H), 7.70 (dd, J=8.9and 2.6 Hz, 1H), 7.41-7.31 (m, 2H), 7.22-7.16 (m, 2H), 5.33 (s, 2H),3.54-3.10 (m, 9H), 1.70-1.15 (m, 10H). MS: m/z 527.3 [M+H]⁺.

Example 1266-Chloro-1-(6-fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.86 (s, 1H), 7.93 (d, J=2.4 Hz, 1H), 7.76 (d, J=4.8Hz, 1H), 7.67 (dd, J=9.0 and 1.8 Hz, 1H), 7.43-7.32 (m, 3H), 7.22-7.19(m, 2H), 7.12 (t, J=4.2 Hz, 1H), 5.33 (s, 2H), 3.54-3.19 (m, 8H). MS:m/z 527.2 [M+H]⁺.

The following compounds were prepared from5-fluoro-1-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione (prepared from5-fluouoquinazoline-2,4(1H,3H)-dione and methyl 3-(bromomethyl)benzoateusing a procedure similar to those used for Examples 1 and 2), and thecorresponding substituted piperazine using a procedure similar to thosedescribed for the synthesis of compound of Example 3.

Example 1275-Fluoro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (CD₃OD): 8.35 (d, J=4.8 Hz, 2H), 7.61 (td, J=8.4 and 5.7 Hz, 1H),7.50-7.32 (m, 4H), 7.06 (d, J=8.4 Hz, 1H), 6.99 (dd, J=10.8 and 8.4 Hz,1H), 6.64 (t, J=4.8 Hz, 1H), 5.48 (s, 2H), 3.89-3.38 (m, 8H). MS: m/z461.2 [M+H]⁺.

Example 1281-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.67 (s, 1H), 7.65-7.57 (m, 1H), 7.41-7.39 (m, 2H),7.31-7.27 (m, 2H), 7.05-6.97 (m, 2H), 5.32 (s, 2H), 3.69-2.90 (m, 9H),1.81-1.51 (m, 8H). MS: m/z 479.3 [M+H]⁺.

Example 1291-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.69 (s, 1H), 7.62 (td, J=8.4 and 6.0 Hz, 1H),7.46-7.41 (m, 2H), 7.32-7.29 (m, 2H), 7.05-6.99 (m, 2H), 5.34 (s, 2H),3.79-3.11 (m, 9H), 1.71-1.61 (m, 5H), 1.33-1.17 (m, 5H). MS: m/z 493.3[M+H]⁺.

Example 1305-Fluoro-1-(3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.67 (s, 1H), 8.10 (d, J=3.6 Hz, 1H), 7.66-7.51 (m,2H), 7.44-7.29 (m, 4H), 7.04-6.98 (m, 2H), 6.80 (d, J=8.7 Hz, 1H), 6.64(t, J=6.6 Hz, 1H), 5.33 (s, 2H), 3.79-3.41 (m, 8H). MS: m/z 460.3[M+H]⁺.

Example 1315-Fluoro-1-(3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.67 (s, 1H), 7.77 (d, J=5.1 Hz, 1H), 7.59 (td, J=6.0and 8.4 Hz, 1H), 7.44-7.29 (m, 5H), 7.14 (d, J=3.9 Hz, 1H), 7.02-6.95(m, 2H), 5.33 (s, 2H), 3.64-3.41 (m, 8H). MS: m/z 493.2 [M+H]⁺.

The following compounds were prepared from1-(3-carboxy-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione(prepared from 5-fluouoquinazoline-2,4(1H,3H)-dione and methyl5-(bromomethyl)-2-fluorobenzoate using a procedure similar to those usedfor Examples 1 and 2), and the corresponding substituted piperazineusing a procedure similar to those described for the synthesis ofcompound of Example 3.

Example 1325-Fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.65 (s, 1H), 8.38 (d, J=4.8 Hz, 2H), 7.95-7.66 (m,1H), 7.47-7.38 (m, 2H), 7.28 (t, J=9.0 Hz, 1H), 7.05-6.99 (m, 2H), 6.66(t, J=4.8 Hz, 1H), 5.30 (s, 2H), 3.82-3.79 (m, 2H), 3.69-3.61 (m, 4H),3.23-3.21 (m, 2H). MS: m/z 479.2 [M+H]⁺.

Example 1331-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.66 (s, 1H), 7.65-7.58 (m, 1H), 7.47-7.41 (m, 1H),7.38 (d, J=5.7 Hz, 1H), 7.27 (t, J=9.0 Hz, 1H), 7.05-6.98 (m, 2H), 5.29(s, 2H), 3.59-2.89 (m, 9H), 1.79-1.45 (m, 8H). MS: m/z 497.3 [M+H]⁺.

Example 1341-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.67 (s, 1H), 7.66-7.59 (m, 1H), 7.47-7.43 (m, 1H),7.38 (d, J=6.0 Hz, 1H), 7.28 (t, J=8.9 Hz, 1H), 7.05-6.99 (m, 2H), 5.30(s, 2H), 3.55-3.12 (m, 9H), 1.62-1.06 (m, 10H). MS: m/z 511.3 [M+H]⁺.

Example 1355-Fluoro-1-(4-fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.65 (s, 1H), 8.11 (dd, J=5.0 and 1.7 Hz, 1H),7.70-7.50 (m, 2H), 7.48-7.37 (m, 2H), 7.27 (t, J=9.0 Hz, 1H), 7.04-6.98(m, 2H), 6.81 (d, J=8.7 Hz, 1H), 6.66 (t, J=5.7 Hz, 1H), 5.29 (s, 2H),3.70-3.68 (m, 2H), 3.57-3.54 (m, 2H), 3.38-3.34 (m, 2H), 3.24-3.22 (m,2H). MS: m/z 478.2 [M+H]⁺.

Example 1365-Fluoro-1-(4-fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.64 (s, 1H), 7.77 (d, J=4.8 Hz, 1H), 7.64-7.56 (m,1H), 7.46-7.37 (m, 3H), 7.27 (t, J=9.0 Hz, 1H), 7.13 (t, J=4.8 Hz, 1H),7.02-6.97 (m, 2H), 5.30 (s, 2H), 3.70-3.23 (m, 8H). MS: m/z 511.2[M+H]⁺.

Example 1371-(3-(4-Benzoylpiperazine-1-carbonyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.67 (s, 1H), 7.60-7.27 (m, 9H), 7.05-6.95 (m, 2H),5.30 (s, 2H), 3.66-3.29 (m, 8H). MS: m/z 505.3 [M+H]⁺.

Compound of Example 138 was prepared from1-(3-carboxybenzyl)-8-fluoroquinazoline-2,4(1H,3H)-dione (prepared from8-fluouoquinazoline-2,4(1H,3H)-dione and methyl 3-(bromomethyl)benzoateusing a procedure similar to those used for Examples 1 and 2), and thecorresponding substituted piperazine using a procedure similar to thosedescribed for the synthesis of compound of Example 3.

Example 1381-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)-8-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.90 (s, 1H), 7.91 (d, J=7.2 Hz, 1H), 7.59-7.51 (m,1H), 7.44-7.33 (m, 2H), 7.29-7.28 (m, 3H), 5.40 (s, 2H), 3.59-3.19 (m,9H), 1.61-1.24 (m, 10H). MS: m/z 493.3 [M+H]⁺.

The following compounds were prepared from6-fluoro-1-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione (prepared from6-fluoroquinazoline-2,4(1H,3H)-dione and methyl 3-(bromomethyl)benzoateusing procedures similar to those of compounds of Examples 1 and 2), andthe corresponding substituted piperazine using a procedure similar tothose described for the synthesis of compound of Example 3.

Example 1396-Fluoro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.86 (s, 1H), 8.38 (d, J=4.5 Hz, 2H), 7.73 (dd, J=8.1and 3.0 Hz, 1H), 7.57 (td, J=9.0 and 3.3 Hz, 1H), 7.36-7.27 (m, 5H),6.67 (t, J=4.7 Hz, 1H), 5.36 (s, 2H), 3.65-3.30 (m, 8H). MS: m/z 461.2[M+H]⁺.

Example 1406-Fluoro-1-(3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.85 (s, 1H), 8.13 (d, J=3.3 Hz, 1H), 7.73 (dd, J=8.4and 3.0 Hz, 1H), 7.61-7.53 (m, 2H), 7.46-7.38 (m, 2H), 7.35-7.28 (m,3H), 6.82 (d, J=8.4 Hz, 1H), 6.67 (t, J=4.8 Hz, 1H), 5.36 (s, 2H),3.76-3.33 (m, 8H). MS: m/z 460.3 [M+H]⁺.

Example 1416-Fluoro-1-(3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.85 (s, 1H), 7.77-7.76 (m, 2H), 7.73 (dd, J=8.4 and3.0 Hz, 1H), 7.54-7.14 (m, 6H), 7.13 (t, J=4.4 Hz, 1H), 5.35 (s, 2H),3.66-3.30 (m, 8H). MS: m/z 493.2 [M+H]⁺.

Example 1421-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.86 (s, 1H), 7.74 (dd, J=8.1 and 3.0 Hz, 1H), 7.56(m, 1H), 7.43-7.41 (m, 2H), 7.32-7.29 (m, 3H), 5.36 (s, 2H), 3.60-3.10(m, 9H), 1.61-1.29 (m, 10H). MS: m/z 493.3 [M+H]⁺.

Example 1431-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (CD₃OD): 7.84 (dd, J=8.4 and 3.0 Hz, 1H), 7.52-7.43 (m, 5H), 7.34(dd, J=9.2 and 4.1 Hz, 1H), 5.46 (s, 2H), 3.72-3.11 (m, 9H), 1.88-1.66(m, 8H). MS: m/z 479.3 [M+H]⁺.

The following compounds were prepared from6-fluoro-1-(3-carboxy-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione(prepared from 6-fluoroquinazoline-2,4(1H,3H)-dione and methyl5-(bromomethyl)-2-fluorobenzoate using procedures similar to those ofcompounds of Examples 1 and 2), and the corresponding substitutedpiperazine using a procedure similar to those described for thesynthesis of compound of Example 3.

Example 1446-Fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.83 (s, 1H), 8.39 (d, J=4.8 Hz, 2H), 7.74 (dd, J=8.4and 3.0 Hz, 1H), 7.60-7.54 (m, 1H), 7.41-7.29 (m, 4H), 6.67 (t, J=4.8Hz, 1H), 5.32 (s, 2H), 3.81-3.23 (m, 8H). MS: m/z 479.3[M+H]⁺.

Example 1456-Fluoro-1-(4-fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.85 (s, 1H), 8.12 (dd, J=4.8 and 1.5 Hz, 1H), 7.72(dd, J=8.3 and 3.2 Hz, 1H), 7.60-7.53 (m, 2H), 7.47-7.40 (m, 2H),7.32-7.26 (m, 2H), 6.83 (d, J=8.7 Hz, 1H), 6.68 (dd, J=6.9 and 5.1 Hz,1H), 5.33 (s, 2H), 3.72-3.25 (m, 8H). MS: m/z 478.3 [M+H]⁺.

Example 1466-Fluoro-1-(4-fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.83 (s, 1H), 7.77-7.70 (m, 2H), 7.57-7.51 (m, 1H),7.41-7.37 (m, 3H), 7.31-7.25 (m, 2H), 7.12 (t, J=4.2 Hz, 1H), 5.31 (s,2H), 3.70-3.16 (m, 8H). MS: m/z 511.2 [M+H]⁺.

Example 1471-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.83 (s, 1H), 7.72 (dd, J=8.3 and 3.2 Hz, 1H),7.57-7.50 (m, 1H), 7.45-7.41 (m, 1H), 7.36 (d, J=6.3 Hz, 1H), 7.29-7.23(m, 2H), 5.30 (s, 2H), 3.53-3.10 (m, 9H), 1.60-1.21 (m, 10H). MS: m/z511.3 [M+H]⁺.

Example 1481-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.83 (s, 1H), 7.73 (dd, J=8.4 and 3.0 Hz, 1H), 7.55(t, J=8.4 Hz, 1H), 7.46-7.42 (m, 1H), 7.36 (d, J=6.0 Hz, 1H), 7.30-7.24(m, 2H), 5.31 (s, 2H), 3.56-3.12 (m, 9H), 1.60-1.56 (m, 8H). MS: m/z479.3 [M+H]⁺.

The following compounds were prepared from6-fluoro-1-(3-carboxy-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione(prepared from 6-fluoroquinazoline-2,4(1H,3H)-dione and methyl3-(bromomethyl)-4-fluorobenzoate using procedures similar to those ofcompounds of Examples 1 and 2), and the corresponding substitutedpiperazine or piperidine using a procedure similar to those describedfor the synthesis of compound of Example 3.

Example 1496-Fluoro-1-(6-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.85 (s, 1H), 8.38 (d, J=4.5 Hz, 2H), 7.74 (dd, J=8.3and 3.2 Hz, 1H), 7.62-7.55 (m, 1H), 7.39-7.33 (m, 2H), 7.30-7.20 (m,2H), 6.66 (t, J=4.8 Hz, 1H), 5.37 (s, 2H), 3.65-3.30 (m, 8H). MS: m/z479.3[M+H]⁺.

Example 1506-Fluoro-1-(6-fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.85 (s, 1H), 8.12 (d, J=3.3 Hz, 1H), 7.74 (d, J=8.4Hz, 1H), 7.63-7.52 (m, 2H), 7.40-7.26 (m, 3H), 7.21 (d, J=7.2 Hz, 1H),6.77 (d, J=8.4 Hz, 1H), 6.66 (t, J=5.9 Hz, 1H), 5.37 (s, 2H), 3.51-3.32(m, 8H). MS: m/z 478.3 [M+H]⁺.

Example 1516-Fluoro-1-(6-fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.83 (s, 1H), 7.75-7.69 (m, 2H), 7.52-7.49 (m, 1H),7.39-7.30 (m, 3H), 7.23-7.17 (m, 2H), 7.11 (t, J=4.2 Hz, 1H), 5.33 (s,2H), 3.70-3.13 (m, 8H). MS: m/z 511.2 [M+H]⁺.

Example 1521-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.86 (s, 1H), 7.76 (dd, J=8.1 and 3.0 Hz, 1H),7.60-7.54 (m, 1H), 7.39-7.35 (m, 2H), 7.24 (dd, J=9.2 and 4.1 Hz, 1H),7.18 (d, J=6.9 Hz, 1H), 5.36 (s, 2H), 3.53-3.10 (m, 9H), 1.70-1.25 (m,10H). MS: m/z 511.3 [M+H]⁺.

Example 1531-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 7.72 (dd, J=8.6 and 3.9 Hz, 1H), 7.58-7.51 (m, 1H),7.36-7.33 (m, 2H), 7.23 (dd, J=9.5 and 3.8 Hz, 1H), 7.16 (d, J=7.2 Hz,1H), 5.33 (s, 2H), 3.31-2.63 (m, 9H), 1.73-1.43 (m, 8H). MS: m/z 479.3[M+H]⁺.

The following compounds were prepared from5-fluoro-1-(3-carboxy-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione andthe corresponding substituted piperazine using a procedure similar tothose described for the synthesis of compound of Example 3.

Example 1545-Fluoro-1-(6-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.68 (s, 1H), 8.38 (d, J=4.5 Hz, 2H), 7.67-7.65 (m,1H), 7.40-7.33 (m, 2H), 7.21 (d, J=7.2 Hz, 1H), 7.08-7.00 (m, 2H), 6.66(t, J=4.8 Hz, 1H), 5.35 (s, 2H), 3.81-3.23 (m, 8H). MS: m/z 479.3[M+H]⁺.

Example 1555-Fluoro-1-(6-fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.66 (s, 1H), 8.10 (d, J=3.3 Hz, 1H), 7.69-7.61 (m,1H), 7.53 (t, J=6.9 Hz, 1H), 7.40-7.31 (m, 2H), 7.21 (d, J=6.6 Hz, 1H),7.08-6.99 (m, 2H), 6.76 (d, J=8.7 Hz, 1H), 6.65 (t, J=6.9 Hz, 1H), 5.34(s, 2H), 3.51-3.30 (m, 8H). MS: m/z 478.3 [M+H]⁺.

Example 1565-Fluoro-1-(6-fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.69 (s, 1H), 7.78 (d, J=4.5 Hz, 1H), 7.64-7.60 (m,1H), 7.38-7.35 (m, 3H), 7.22 (d, J=6.0 Hz, 1H), 7.16-7.13 (m, 1H),7.00-6.94 (m, 2H), 5.33 (s, 2H), 3.32-3.15 (m, 8H). MS: m/z 511.2[M+H]⁺.

Example 1571-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.70 (s, 1H), 7.68-7.61 (m, 1H), 7.39-7.33 (m, 2H),7.21 (d, J=7.2 Hz, 1H), 7.06-6.97 (m, 2H), 5.34 (s, 2H), 3.53-3.10 (m,9H), 1.70-1.24 (m, 10H). MS: m/z 511.3 [M+H]⁺.

Example 1581-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.68 (s, 1H), 7.67-7.60 (m, 1H), 7.41-7.32 (m, 2H),7.20 (d, J=7.5 Hz, 1H), 7.06-6.97 (m, 2H), 5.33 (s, 2H), 3.60-3.15 (m,9H), 1.60-1.55 (m, 8H). MS: m/z 497.3 [M+H]⁺.

The following compounds were prepared from5-methyl-1-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione and thecorresponding substituted piperazine using a procedure similar to thosedescribed for the synthesis of compound of Example 3.

Example 1595-Methyl-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (CD₃OD): 8.37 (d, J=4.8 Hz, 2H), 7.49-7.47 (m, 3H), 7.42-7.36 (m,2H), 7.14-7.08 (m, 2H), 6.66 (t, J=5.0 Hz, 1H), 5.46 (s, 2H), 3.91-3.62(m, 8H), 2.79 (s, 3H). MS: m/z 457.3 [M+H]⁺.

Example 1601-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)-5-methylquinazoline-2,4(1H,3H)-dione

¹H NMR (CD₃OD): 7.49-7.36 (m, 5H), 7.14-7.08 (m, 2H), 5.46 (s, 2H),3.82-3.10 (m, 9H), 2.80 (s, 3H), 1.88-1.56 (m, 8H). MS: m/z 475.3[M+H]⁺.

The following compounds were prepared from1-(3-carboxybenzyl)-7-chloroquinazoline-2,4(1H,3H)-dione and thecorresponding substituted piperazine using a procedure similar to thosedescribed for the synthesis of compound of Example 3.

Example 1617-Chloro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.81 (s, 1H), 8.37 (d, J=4.8 Hz, 2H), 8.00 (d, J=8.4Hz, 1H), 7.40-7.27 (m, 6H), 6.65 (t, J=4.7 Hz, 1H), 5.36 (s, 2H),3.77-3.63 (m, 8H). MS: m/z 477.2 [M+H]⁺.

Example 1627-Chloro-1-(3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.85 (s, 1H), 8.02 (d, J=9.0 Hz, 1H), 7.44-7.29 (m,6H), 5.36 (s, 2H), 3.40-3.10 (m, 9H), 1.81-1.51 (m, 8H). MS: m/z 495.3[M+H]⁺.

The following compounds were prepared from the corresponding substituted1-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione and substitutedpiperazine using a procedure similar to those described for thesynthesis of compound of Example 3.

Example 1631-(3-(4-(Cyclopropylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.65 (s, 1H), 7.65-7.57 (m, 1H), 7.46-7.41 (m, 1H),7.38-7.35 (m, 1H), 7.30-7.23 (m, 1H), 7.04-6.98 (m, 2H), 5.29 (s, 2H),3.75-3.15 (m, 8H), 1.99-1.96 (m, 1H), 0.72-0.69 (m, 4H). MS: m/z 469.5[M+H]⁺.

Example 1646-Chloro-1-(3-(4-benzoylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.85 (s, 1H), 7.91 (s, 1H), 7.68-7.62 (m, 1H),7.44-7.35 (m, 7H), 7.28-7.22 (m, 2H), 5.29 (s, 2H), 3.64-3.21 (m, 8H).MS: m/z 521.5 [M+H]⁺.

Example 1651-(3-(4-(Cyclobutylcarbonyl)piperazine-1-carbonyl)benzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.66 (s, 1H), 7.64-7.57 (m, 1H), 7.43-7.36 (m, 2H),7.29-7.26 (m, 2H), 7.04-6.98 (m, 2H), 5.32 (s, 2H), 3.56-3.00 (m, 9H),2.17-1.66 (m, 6H). MS: m/z 465.6 [M+H]⁺.

Example 1661-(3-(4-(Cyclobutylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.65 (s, 1H), 7.65-7.57 (m, 1H), 7.46-7.40 (m, 1H),7.36 (d, J=5.4 Hz, 1H), 7.26 (t, J=9.0 Hz, 1H), 7.04-6.99 (m, 2H), 5.28(s, 2H), 3.55-3.09 (m, 9H), 2.18-1.67 (m, 6H). MS: m/z 483.3 [M+H]⁺.

Example 1676-Chloro-1-(3-(4-(cyclobutylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.87 (s, 1H), 7.95 (d, J=2.4 Hz, 1H), 7.69 (dd, J=8.9and 2.6 Hz, 1H), 7.42-7.30 (m, 2H), 7.22-7.15 (m, 2H), 5.33 (s, 2H),3.55-3.09 (m, 9H), 2.14-1.72 (m, 6H). MS: m/z 499.3 [M+H]⁺.

Example 1685-Chloro-1-(3-(4-(cyclobutylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.69 (s, 1H), 7.55 (t, J=8.3 Hz, 1H), 7.46-7.42 (m,1H), 7.37 (d, J=6.3 Hz, 1H), 7.30-7.24 (m, 2H), 7.18-7.13 (m, 1H), 5.31(s, 2H), 3.56-3.11 (m, 9H), 2.10-1.73 (m, 6H). MS: m/z 499.3 [M+H]⁺.

Example 1696-Chloro-1-(3-(4-(cyclobutylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.88 (s, 1H), 7.94 (s, 1H), 7.70 (dd, J=9.0 and 2.7Hz, 1H), 7.46-7.42 (m, 1H), 7.36 (dd, J=6.3 and 1.8 Hz, 1H), 7.31-7.21(m, 2H), 5.30 (s, 2H), 3.56-3.11 (m, 9H), 2.50-1.73 (m, 6H). MS: m/z499.3 [M+H]⁺.

Example 1705-Chloro-1-(3-(4-(cyclobutylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.69 (s, 1H), 7.57 (t, J=8.3 Hz, 1H), 7.38-7.29 (m,3H), 7.20 (d, J=6.9 Hz, 1H), 7.15 (d, J=8.7 Hz, 1H), 5.35 (s, 2H),3.56-3.00 (m, 9H), 2.12-1.74 (m, 6H). MS: m/z 499.4 [M+H]⁺.

Example 1715-Chloro-1-(6-fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.72 (s, 1H), 7.79 (d, J=5.1 Hz, 1H), 7.54 (t, J=8.3Hz, 1H), 7.39-7.36 (m, 3H), 7.23 (m, 2H), 7.14-7.11 (m, 2H), 5.35 (s,2H), 3.66-3.10 (m, 8H). MS: m/z 527.2 [M+H]⁺.

Example 1725-Fluoro-1-(4-fluoro-3-(4-(furan-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.67 (s, 1H), 7.85 (s, 1H), 7.66-7.58 (m, 1H),7.46-7.39 (m, 2H), 7.29 (t, J=9.0 Hz, 1H), 7.04-6.98 (m, 3H), 6.64-6.63(m, 1H), 5.31 (s, 2H), 3.73-3.70 (m, 4H), 3.55-3.54 (m, 2H), 3.23-3.22(m, 2H). MS: m/z 495.3 [M+H]⁺.

Example 1735-Chloro-1-(6-fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.70 (s, 1H), 8.12 (dd, J=4.8 and 1.2 Hz, 1H),7.62-7.52 (m, 2H), 7.45-7.31 (m, 3H), 7.22 (d, J=7.5 Hz, 1H), 7.15 (d,J=8.4 Hz, 1H), 6.75 (d, J=8.7 Hz, 1H), 6.68-6.64 (m, 1H), 5.36 (s, 2H),3.69-3.21 (m, 8H). MS: m/z 494.3 [M+H]⁺.

Example 1746-Chloro-1-(6-fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.86 (s, 1H), 8.08 (d, J=3.9 Hz, 1H), 7.92 (d, J=2.4Hz, 1H), 7.72 (dd, J=9.0 and 2.4 Hz, 1H), 7.66-7.59 (m, 1H), 7.44-7.32(m, 2H), 7.24 (d, J=9.0 Hz, 1H), 7.20 (d, J=7.8 Hz, 1H), 6.84 (d, J=7.5Hz, 1H), 6.70 (t, J=5.4 Hz, 1H), 5.34 (s, 2H), 3.69-3.21 (m, 8H). MS:m/z 494.3 [M+H]⁺.

Example 1756-Chloro-1-(5-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.83 (s, 1H), 8.36 (d, J=4.8 Hz, 2H), 7.92 (d, J=2.4Hz, 1H), 7.70 (d, J=8.7 Hz, 1H), 7.24-7.18 (m, 4H), 6.64 (t, J=4.8 Hz,1H), 5.34 (s, 2H), 3.69-3.21 (m, 8H). MS: m/z 495.3 [M+H]⁺.

Example 1765-Fluoro-1-(5-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.63 (s, 1H), 8.36 (d, J=4.8 Hz, 2H), 7.66-7.61 (m,1H), 7.29 (d, J=9.3 Hz, 1H), 7.19-7.16 (m, 2H), 7.05-6.98 (m, 2H), 6.65(t, J=4.8 Hz, 1H), 5.33 (s, 2H), 3.80-3.20 (m, 8H). MS: m/z 479.3[M+H]⁺.

Example 1771-(3-(4-Cyclopentylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.71 (s, 1H), 8.02 (dd, J=8.0 and 1.4 Hz, 1H), 7.63(t, J=7.1 Hz, 1H), 7.43-7.36 (m, 2H), 7.26-7.21 (m, 4H), 5.34 (s, 2H),3.65-3.30 (m, 9H), 1.48-1.22 (m, 8H). MS: m/z 433.3 [M+H]⁺.

Example 1781-(3-(4-(Cyclopropylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.84 (s, 1H), 7.74 (dd, J=8.1 and 3.0 Hz, 1H), 7.56(t, J=8.4 Hz, 1H), 7.45-7.39 (m, 2H), 7.31-7.25 (m, 2H), 5.32 (s, 2H),3.54-3.16 (m, 8H), 1.92 (m, 1H), 0.73-0.70 (m, 4H). MS: m/z 469.3[M+H]⁺.

Example 1791-(3-(4-(Cyclobutylcarbonyl)piperazine-1-carbonyl)benzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.86 (s, 1H), 7.75 (dd, J=8.3 and 2.9 Hz, 1H), 7.56(t, J=8.7 Hz, 1H), 7.43-7.40 (m, 2H), 7.31-7.26 (m, 3H), 5.35 (s, 2H),3.52-3.31 (m, 9H), 2.18-1.75 (m, 6H). MS: m/z 465.3 [M+H]⁺.

Example 1801-(3-(4-(Cyclobutylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.84 (s, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.59-7.53 (m,1H), 7.46-7.44 (m, 1H), 7.37 (d, J=5.7 Hz, 1H), 7.31-7.25 (m, 2H), 5.31(s, 2H), 3.57-3.11 (m, 9H), 2.14-1.74 (m, 6H). MS: m/z 483.3 [M+H]⁺.

Example 1811-(3-(4-Benzoylpiperazine-1-carbonyl)-4-fluorobenzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.84 (s, 1H), 7.74 (dd, J=8.1 and 2.7 Hz, 1H),7.55-7.53 (m, 1H), 7.46-7.42 (m, 7H), 7.30-7.24 (m, 2H), 5.31 (s, 2H),3.67-3.20 (m, 8H). MS: m/z 505.3 [M+H]⁺.

Example 1821-(3-(4-(Cyclobutylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.68 (s, 1H), 7.66-7.59 (m, 1H), 7.36-7.33 (m, 2H),7.18 (d, J=7.2 Hz, 1H), 7.07-6.96 (m, 2H), 5.32 (s, 2H), 3.60-3.01 (m,9H), 2.11-1.73 (m, 6H). MS: m/z 483.4 [M+H]⁺.

Example 1831-(3-(4-(Cyclobutylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.84 (s, 1H), 7.73 (dd, J=8.1 and 2.7 Hz, 1H), 7.56(t, J=8.4 Hz, 1H), 7.36-7.30 (m, 2H), 7.24-7.14 (m, 2H), 5.34 (s, 2H),3.60-3.01 (m, 9H), 2.14-1.72 (m, 6H). MS: m/z 483.3 [M+H]⁺.

Example 1845-Fluoro-1-(6-fluoro-3-(4-(furan-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.70 (s, 1H), 7.86 (s, 1H), 7.67-7.59 (m, 1H),7.39-7.36 (m, 2H), 7.23 (d, J=7.2 Hz, 1H), 7.05-6.97 (m, 3H), 6.65-6.63(m, 1H), 5.34 (s, 2H), 3.70-3.10 (m, 8H). MS: m/z 495.4 [M+H]⁺.

Example 1856-Fluoro-1-(4-fluoro-3-(4-(furan-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.84 (s, 1H), 7.84 (s, 1H), 7.74 (dd, J=8.4 and 3.0Hz, 1H), 7.59-7.53 (m, 1H), 7.45-7.39 (m, 2H), 7.32-7.26 (m, 2H), 7.02(d, J=3.3 Hz, 1H), 6.63 (dd, J=3.3 Hz and 1.8 Hz, 1H), 5.32 (s, 2H),3.67-3.23 (m, 8H). MS: m/z 495.3 [M+H]⁺.

Example 1866-Fluoro-1-(5-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.83 (s, 1H), 8.39 (d, J=4.5 Hz, 2H), 7.74 (dd, J=8.3and 3.2 Hz, 1H), 7.60-7.54 (m, 1H), 7.33-7.29 (m, 2H), 7.27-7.18 (m,2H), 6.67 (t, J=4.8 Hz, 1H), 5.36 (s, 2H), 3.80-3.35 (m, 8H). MS: m/z479.4 [M+H]⁺.

Example 1871-(6-Chloro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.86 (s, 1H), 8.37 (d, J=4.8 Hz, 2H), 7.76-7.69 (m,1H), 7.65 (d, J=8.1 Hz, 1H), 7.60-7.59 (m, 1H), 7.38 (dd, J=8.3 and 1.7Hz, 1H), 7.13-7.09 (m, 2H), 6.65 (t, J=4.7 Hz, 1H), 5.32 (s, 2H),3.73-3.03 (m, 8H). MS: m/z 495.3 [M+H]⁺.

Example 1886-Fluoro-1-(4-fluoro-3-(4-(thiazol-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.82 (s, 1H), 7.71 (dd, J=8.4 and 3.0 Hz, 1H),7.58-7.51 (m, 1H), 7.43-7.38 (m, 2H), 7.30-7.23 (m, 2H), 7.17 (d, J=3.6Hz, 1H), 6.88 (d, J=3.6 Hz, 1H), 5.30 (s, 2H), 3.73-3.26 (m, 8H). MS:m/z 484.3 [M+H]⁺.

Example 1895-Fluoro-1-(4-fluoro-3-(4-(thiazol-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.65 (s, 1H), 7.65-7.57 (m, 1H), 7.43-7.38 (m, 2H),7.27 (t, J=9.0 Hz, 1H), 7.17 (d, J=3.6 Hz, 1H), 7.04-6.98 (m, 2H), 6.87(d, J=3.6 Hz, 1H), 5.29 (s, 2H), 3.73-3.26 (m, 8H). MS: m/z 484.3[M+H]⁺.

Example 1901-(4-Fluoro-3-(4-(thiazol-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.70 (s, 1H), 8.00 (d, J=8.1 Hz, 1H), 7.64 (t, J=7.9Hz, 1H), 7.46-7.38 (m, 2H), 7.30-7.22 (m, 3H), 7.17 (d, J=3.6 Hz, 1H),6.87 (d, J=3.6 Hz, 1H), 5.31 (s, 2H), 3.79-3.23 (m, 8H). MS: m/z 466.3[M+H]⁺.

Example 1911-(3-(4-(Cyclohexylcarbamoyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.67 (s, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.63 (t, J=7.8Hz, 1H), 7.40-7.37 (m, 2H), 7.30-7.22 (m, 4H), 6.20 (d, J=4.0 Hz, 1H),5.33 (s, 2H), 3.80-3.00 (m, 9H), 1.80-1.00 (m, 10H). MS: m/z 490.4[M+H]⁺.

The following salts were prepared from the corresponding free base viastirring the free base in HCl/ethyl acetate for 2.5 h at roomtemperature, followed by evaporation of the solvents.

Example 1921-(4-Fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dionehydrochloride

¹H NMR (DMSO-d₆): 11.71 (s, 1H), 8.38 (d, J=4.8 Hz, 2H), 8.00 (d, J=6.9Hz, 1H), 7.64 (t, J=7.8 Hz, 1H), 7.46-7.39 (m, 2H), 7.30-7.21 (m, 3H),6.67 (t, J=4.8 Hz, 1H), 5.31 (s, 2H), 3.81-3.78 (m, 2H), 3.67-3.62 (m,4H), 3.24-3.20 (m, 2H). MS: m/z 461.2 [M+H]⁺.

Example 1935-Fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dionehydrochloride

¹H NMR (DMSO-d₆): 11.66 (s, 1H), 8.41 (d, J=4.5 Hz, 2H), 7.67-7.59 (m,1H), 7.47-7.39 (m, 2H), 7.28 (t, J=4.5 Hz, 1H), 7.06-6.99 (m, 2H), 6.70(t, J=4.8 Hz, 1H), 5.31 (s, 2H), 3.82-3.81 (m, 2H), 3.69-3.64 (m, 4H),3.25-3.22 (m, 2H). MS: m/z 479.3 [M+H]⁺.

Example 1941-(3-(4-(Pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dionehydrochloride

¹H NMR (DMSO-d₆): 11.72 (s, 1H), 8.37 (d, J=4.8 Hz, 2H), 8.01 (d, J=6.9Hz, 1H), 7.64 (t, J=6.9 Hz, 1H), 7.50-7.20 (m, 6H), 6.66 (t, J=4.7 Hz,1H), 5.35 (s, 2H), 4.10-3.20 (m, 8H). MS: m/z 443.3 [M+H]⁺.

Example 1951-(3-((4-(Pyridin-2-yl)piperazin-1-yl)methyl)benzyl)quinazoline-2,4(1H,3H)-dione

-   a) 1-(3-(Hydroxymethyl)benzyl)quinazoline-2,4(1H,3H)-dione: To the    solution of 1-(3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione    (0.5 g, 1.6 mmol) in THF (30 mL) and ethanol (10 mL) was added NaBH₄    (1.2 g, 32 mmol) at room temperature under N₂. It was stirred at    room temperature for 4 h, then refluxed overnight. The reaction    mixture was quenched with HCl (2N), then concentrated. The residue    was diluted with H₂O (10 mL), and it was extracted with ethyl    acetate (3×10 mL). The combined organic layers were washed with    brine, dried over anhydrous Na₂SO₄, and concentrated to afford the    crude product, which was used for the next reaction without    purification.-   b) 1-(3-(Methanesulfonoylmethyl)benzyl)quinazoline-2,4(1H,3H)-dione:    To a solution of    1-(3-(hydroxymethyl)benzyl)quinazoline-2,4(1H,3H)-dione (0.1 g, 0.35    mmol) and triethylamine (0.1 g, 1.1 mmol) in dry DCM (2 mL) was    added MsCl dropwise at 0° C. under N₂. The mixture was stirred for 2    h, and was used for the next reaction directly.-   c)    1-(3-((4-(Pyridin-2-yl)piperazin-1-yl)methyl)benzyl)quinazoline-2,4(1H,3H)-dione:    A solution of 1-(pyridin-2-yl)piperazine (0.057 g, 0.35 mmol) in dry    DCM (0.2 mL) was added to the above solution at room temperature    under N₂, and the mixture was refluxed overnight. The reaction    mixture was concentrated, and the residue was diluted with H₂O (2    mL). It was extracted with ethyl acetate (3×10 mL). The combined    organic layers was washed with brine, dried with anhydrous Na₂SO₄,    and concentrated. The crude product was purified by preparative TLC    to give the title compound (5 mg) as white solid. ¹H NMR (DMSO-d₆):    8.09 (d, J=3.3 Hz, 1H), 8.02 (d, J=6.6 Hz, 1H), 7.66-7.61 (m, 1H),    7.54-7.48 (m, 1H), 7.29-7.15 (m, 6H), 6.78 (d, J=8.7 Hz, 1H),    6.64-6.59 (m, 1H), 5.32 (s, 2H), 3.42-3.39 (m, 4H), 2.40-2.37 (m,    4H). MS: m/z 428.3 [M+H]⁺.

The following compounds were prepared from1-(3-aminobenzyl)quinazoline-2,4(1H,3H)-dione (prepared fromquinazoline-2,4(1H,3H)-dione and 1-(bromomethyl)-3-nitrobenzene followedby reduction) and the corresponding substituted acetic acid using aprocedure similar to those described for the synthesis of compound ofExample 3.

Example 1961-(3-(Naphthalen-2-yl)acetamidobenzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.72 (brs, 1H), 10.23 (s, 1H), 8.10-7.99 (m, 1H),7.90-7.76 (m, 4H), 7.62-7.56 (m, 2H), 7.46-7.38 (m, 4H), 7.26-7.16 (m,3H), 7.05-6.90 (m, 1H), 5.25 (s, 2H), 3.75 (s, 2H). MS: m/z 436.4[M+H]⁺.

Example 1971-(3-(3,4-Dimethoxyphenyl)acetamidobenzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.70 (brs, 1H), 10.03 (s, 1H), 8.01 (dd, J=7.8 and1.2 Hz, 1H), 7.65-7.55 (m, 2H), 7.34 (s, 1H), 7.27-7.17 (m, 3H), 6.98(d, J=7.8 Hz, 1H), 6.83-6.77 (m, 3H), 5.26 (s, 2H), 3.69 (s, 6H), 3.47(s, 2H). MS: m/z 446.3 [M+H]⁺.

Example 1981-(3-([1,2,4]Triazolo[4,3-a]pyridine-6-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

-   a)    1-(3-(N-Methoxy-N-methylcarbamoyl)benzyl)quinazoline-2,4(1H,3H)-dione:    To a solution of 1-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione    (0.5 g, 1.68 mmol), HATU (0.96 g, 2.53 mmol) and DIEA (0.9 g, 7    mmol) in dry DCM (20 mL) was added N,O-dimethylhydroxylamine    hydrochloride (0.2 g, 2.0 mmol) at room temperature under N₂, then    the mixture was heated to 4° C. and stirred overnight. The reaction    solution was concentrated, the residue was diluted with H₂O and it    was extracted with ethyl acetate (3×10 mL). The combined organic    layers were washed with water and brine, dried over anhydrous Na₂SO₄    and concentrated. The crude product was purified via chromatography    to give the title compound (0.4 g, 70% yield).-   b)    1-(3-([1,2,4]triazolo[4,3-a]pyridine-6-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione:    To a solution of 6-bromo-[1,2,4]triazolo[4,3-a]pyridine (35 mg, 0.18    mmol) in anhydrous THF (1 mL) was added n-BuLi (0.15 mL, 0.38 mmol)    dropwise at −65° C. under N₂, then it was maintained at this    temperature for 3 h. To this solution was added dropwise a solution    of    1-(3-(N-methoxy-N-methylcarbamoyl)benzyl)quinazoline-2,4(1H,3H)-dione    (50 mg, 0.15 mmol) in THF (1 mL), then it was stirred for 4 h at    −65° C. It was allowed to warm to 0° C. for over 4 h. The reaction    solution was poured into saturated aqueous NH₄Cl, extracted with    ethyl acetate (3×10 mL). The combined organic layers were washed    with brine, dried over anhydrous Na₂SO₄, and concentrated. The crude    product was purified by preparative TLC to give the title compound    (6.5 mg, 11% yield) as white solid. ¹H NMR (CD₃OD+CDCl₃): 9.42 (d,    J=7.2 Hz, 1H), 8.41-8.39 (m, 2H), 8.10 (d, J=7.2 Hz, 1H), 7.95 (d,    J=9.0 Hz, 1H), 7.58-7.45 (m, 4H), 7.18-7.11 (m, 3H), 5.38 (s, 2H).    MS: m/z 398.2 [M+H]⁺.

The following compounds were prepared from the corresponding substituted1-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione or1-((2-carboxylpyridin-6-yl)methyl)quinazoline-2,4(1H,3H)-dione andsubstituted amine using a procedure similar to those described for thesynthesis of compound of Example 3.

Example 1996-Fluoro-1-((2-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)pyridin-6-yl)methyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.84 (s, 1H), 8.39 (d, J=4.8 Hz, 2H), 7.94 (t, J=7.8Hz, 1H), 7.72-7.70 (m, 1H), 7.57-7.53 (m, 3H), 7.34-7.30 (m, 1H), 6.67(t, J=4.8 Hz, 1H), 5.46 (s, 2H), 3.73-3.63 (m, 4H), 3.42-3.32 (m, 4H).MS: m/z 462.5 [M+E1]⁺.

Example 2005-Fluoro-1-(4-fluoro-3-(4-methoxybenzylcarbamoyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.70 (s, 1H), 8.79 (t, J=5.3 Hz, 1H), 7.66-7.57 (m,2H), 7.46-7.41 (m, 1H), 7.27-7.20 (m, 3H), 7.08-6.99 (m, 2H), 6.90-6.87(m, 2H), 5.30 (s, 2H), 4.37 (d, J=6.0 Hz, 2H), 3.73 (s, 3H). MS: m/z452.2 [M+H]⁺.

Example 2011-(3-(3-Chlorobenzylcarbamoyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.70 (s, 1H), 9.01 (t, J=5.1 Hz, 1H), 7.75-7.68 (m,2H), 7.57-7.52 (m, 1H), 7.48-7.32 (m, 5H), 7.18-7.08 (m, 2H), 5.31 (s,2H), 4.45 (d, J=5.7 Hz, 2H). MS: m/z 456.1 [M+H]⁺.

Example 2021-(3-(Benzylcarbamoyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.70 (s, 1H), 8.87 (t, J=5.1 Hz, 1H), 7.67-7.59 (m,2H), 7.47-7.42 (m, 1H), 7.36-7.22 (m, 6H), 7.09-6.99 (m, 2H), 5.31 (s,2H), 4.45 (d, J=6.0 Hz, 1H). MS: m/z 422.3 [M+H]⁺.

Example 2035-Methoxy-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.32 (s, 1H), 8.38 (d, J=4.8 Hz, 2H), 7.53 (t, J=8.4Hz, 1H), 7.44-7.29 (m, 4H), 6.85 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.4 Hz,1H), 6.67 (t, J=4.8 Hz, 1H), 5.33 (s, 2H), 3.84 (s, 3H), 3.79-3.42 (m,8H). MS: m/z 473.3 [M+H]⁺.

Example 2046-Methoxy-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.71 (s, 1H), 8.38 (d, J=4.8 Hz, 2H), 7.47-7.40 (m,3H), 7.34-7.26 (m, 3H), 7.20 (d, J=9.3 Hz, 1H), 6.67 (t, J=4.8 Hz, 1H),5.35 (s, 2H), 3.80 (s, 3H), 3.63-3.46 (m, 8H). MS: m/z 473.3 [M+H]⁺.

Example 2051-(3-(5-Bromopyrimidin-2-aminocarbamoyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.73 (s, 1H), 10.27 (s, 1H), 9.43 (s, 1H), 8.50 (s,2H), 7.68-7.52 (m, 3H), 7.28 (t, J=9.3 Hz, 1H), 7.11-7.00 (m, 2H), 5.33(s, 2H). MS: m/z 503.0 [M+H]⁺.

Example 2061-(3-(4-(Pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (300 M, DMSO-d₆): δ11.96 (s, 1H), 8.36 (d, J=4.8 Hz, 2H), 8.19(d, J=8.1 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.47 (s, 1H), 7.43-7.39 (m,3H), 7.33-7.30 (m, 1H), 6.65 (t, J=4.7 Hz, 1H), 5.44 (s, 2H), 3.59-3.46(m, 8H). MS: m/z 511.2 [M+H]⁺.

Example 2076,7-Ethylenedioxo-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.55 (s, 1H), 8.39 (d, J=4.8 Hz, 2H), 7.44-7.34 (m,5H), 6.75 (s, 1H), 6.67 (t, J=4.8 Hz, 1H), 5.29 (s, 2H), 4.32-4.27 (m,4H), 3.88-3.56 (m, 8H). MS: m/z 501.2 [M+H]⁺.

Example 2085-Fluoro-1-(6-methoxy-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.65 (s, 1H), 8.37 (d, J=4.8 Hz, 2H), 7.67-7.60 (m,1H), 7.39 (dd, J=8.4 and 1.8 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.07-6.98(m, 2H), 6.87 (d, J=8.4 Hz, 1H), 6.65 (t, J=4.7 Hz, 1H), 5.20 (s, 2H),3.95 (s, 3H), 3.82-3.16 (m, 8H). MS: m/z 491.2 [M+H]⁺.

Example 2097-Methoxy-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.54 (s, 1H), 8.37 (d, J=4.8 Hz, 2H), 7.92 (d, J=8.7Hz, 1H), 7.42-7.30 (m, 4H), 6.84 (dd, J=8.9 and 2.3 Hz, 1H), 6.68-6.63(m, 2H), 5.34 (s, 2H), 3.76 (s, 3H), 3.71-3.51 (m, 8H). MS: m/z473.3[M+H]⁺

Example 2105-Fluoro-1-(4-fluoro-3-(4-(tetrahydrofuran-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.67 (s, 1H), 7.66-7.59 (m, 1H), 7.47-7.42 (m, 1H),7.38 (d, J=6.0 Hz, 1H), 7.28 (t, J=9.0 Hz, 1H), 7.10-6.95 (m, 2H), 5.30(s, 2H), 4.75-4.50 (m, 1H), 3.85-3.45 (m, 8H), 3.25-3.00 (m, 2H),2.15-1.70 (m, 4H). MS: m/z 499.3 [M+H]⁺.

Example 2115-Fluoro-1-(4-nitro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.71 (s, 1H), 8.40 (d, J=3.9 Hz, 2H), 8.17 (d, J=8.7Hz, 1H), 7.63-7.57 (m, 3H), 7.07-6.94 (m, 2H), 6.69 (t, J=4.4 Hz, 1H),5.45 (s, 2H), 3.85-3.84 (m, 2H), 3.70-3.69 (m, 2H), 3.61-3.59 (m, 2H),3.21-3.18 (m, 2H). MS: m/z 506.2 [M+H]⁺.

Example 2121-(3-(4-Cyclohexylpiperazine-1-carbonyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.68 (s, 1H), 7.66-7.58 (m, 1H), 7.45-7.40 (m, 1H),7.30-7.23 (m, 2H), 7.06-6.99 (m, 2H), 5.30 (s, 2H), 3.56-3.07 (m, 8H),2.33-2.25 (m, 1H), 1.72-1.04 (m, 10H). MS: m/z 483.5 [M+H]⁺.

Example 2135-Fluoro-1-(4-fluoro-3-(4-phenylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.68 (s, 1H), 7.67-7.60 (m, 1H), 7.48-7.38 (m, 2H),7.32-7.20 (m, 3H), 7.07-7.00 (m, 2H), 6.94-6.91 (m, 2H), 6.82 (t, J=7.2Hz, 1H), 5.31 (s, 2H), 3.85-3.65 (m, 2H), 3.45-3.10 (m, 4H), 3.10-2.90(m, 2H). MS: m/z 477.4 [M+H]⁺.

Example 2145-Fluoro-1-(4-fluoro-3-(4-phenylpiperidine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.68 (s, 1H), 7.62-7.56 (m, 1H), 7.45-7.37 (m, 2H),7.33-7.18 (m, 6H), 7.04-6.93 (m, 2H), 5.45-5.15 (m, 2H), 4.70-4.55 (m,1H), 3.50-3.05 (m, 2H), 2.95-2.65 (m, 2H), 1.80-1.20 (m, 4H). MS: m/z476.4 [M+H]⁺.

Example 2151-(4-Bromo-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.67 (s, 1H), 8.39 (d, J=4.8 Hz, 2H), 7.66-7.58 (m,2H), 7.37 (d, J=1.8 Hz, 1H), 7.30 (dd, J=8.4 and 2.1 Hz, 1H), 7.06-6.97(m, 2H), 6.68 (t, J=4.8 Hz, 1H), 5.37-5.22 (m, 2H), 3.82-3.11 (m, 8H).MS: m/z 539.3 [M+H]⁺.

Example 2166,7-Methylenedioxo-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.64 (s, 1H), 8.39 (d, J=4.5 Hz, 2H), 7.44-7.32 (m,5H), 6.95 (s, 1H), 6.67 (t, J=4.4 Hz, 1H), 6.14 (s, 2H), 5.33 (s, 2H),3.81-3.65 (m, 8H). MS: m/z 487.2 [M+H]⁺.

Example 2171-(3-(4-(Cyclohexylmethyl)piperazine-1-carbonyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.70 (s, 1H), 7.66-7.58 (m, 1H), 7.44-7.40 (m, 1H),7.32-7.23 (m, 2H), 7.05-6.99 (m, 2H), 5.30 (s, 2H), 3.70-3.50 (m, 2H),3.20-3.00 (m, 2H), 2.38-2.28 (m, 2H), 2.20-2.10 (m, 2H), 2.05 (d, J=6.6Hz, 2H), 1.73-1.63 (m, 5H), 1.45-1.39 (m, 1H), 1.30-1.00 (m, 3H),0.90-0.70 (m, 2H). MS: m/z 497.3 [M+H]⁺.

Example 2188-Fluoro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (DMSO-d₆): 11.93 (s, 1H), 8.38 (d, J=4.8 Hz, 2H), 7.89 (d, J=7.8Hz, 1H), 7.60-7.52 (m, 1H), 7.45-7.22 (m, 5H), 6.66 (t, J=4.8 Hz, 1H),5.40 (s, 2H), 3.90-3.20 (m, 8H). MS: m/z 461.2 [M+H]⁺.

Example 2196-Amino-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

A mixture of6-nitro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-quinazoline-2,4(1H,3H)-dione(50 mg, 0.10 mmol) in EtOH (10 mL) with Fe powder (33.5 mg, 0.60 mmol)and sat. NH₄Cl solution (0.2 mL) were refluxed under N₂ overnight. Themixture was filtered to remove the solid. The solution was concentratedand purified by flash chromatography (DCM:MeOH=50:3) to give the titlecompound (10.79 mg, 23.6% yield) as yellow solid. ¹H NMR (DMSO-d₆):11.46 (s, 1H), 8.39 (d, J=4.8 Hz, 2H), 7.42-7.31 (m, 4H), 7.20 (d, J=2.7Hz, 1H), 7.00 (d, J=8.7 Hz, 1H), 6.89 (dd, J=8.7 and 2.7 Hz, 1H), 6.67(t, J=4.8 Hz, 1H), 5.26 (s, 4H), 3.81-3.68 (m, 8H). MS: m/z 458.3[M+H]⁺.

Example 2201-(2-(4-(Pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

The title compound was prepared from1-(2-carboxybenzyl)quinazoline-2,4(1H,3H)-dione (prepared fromquinazoline-2,4(1H,3H)-dione and methyl 2-(bromomethyl)benzoate using aprocedure similar to those used for compounds of Example 1 and 2), and2-(piperazin-1-yl)pyrimidine using a procedure similar to that describedfor the synthesis of compound of Example 3. ¹H NMR (DMSO-d₆): 11.76 (s,1H), 8.40 (d, J=4.8 Hz, 2H), 8.03-8.00 (m, 1H), 7.70-7.50 (m, 1H),7.35-7.00 (m, 6H), 6.68 (t, J=4.8 Hz, 1H), 5.25 (s, 2H), 4.10-3.60 (m,8H). MS: m/z 443.2 [M+H]⁺.

Example 2211-(3-(4-(Pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)quinazoline-2,4(1H,3H)-dione

-   a) Methyl 3-(3-(2-bromobenzoyl)ureido)benzoate: To a solution of    2-bromobenzamide (2.0 g, 10.0 mmol) in DCM (30 mL) was added oxalyl    chloride (1.65 g, 13.0 mmol) and it was heated under reflux for    23 h. To the reaction mixture was added methyl 3-aminobenzoate (1.66    g, 11.0 mmol) and it was stirred for 20 min. The mixture was poured    into water, and the precipitate was filtered. It was recrystallized    from ethanol to give the crude product (1.80 g, 48%), which was used    for the next step without further purification.-   b) 1-(3-Methoxycarbonylphenyl)quinazoline-2,4(1H,3H)-dione: A    mixture of methyl 3-(3-(2-bromobenzoyl)ureido)benzoate (1.8 g, 4.8    mmol), potassium tert-butoxide (2.69 g, 24 mmol) and DMF (20 mL) was    stirred at 70-80° C. under nitrogen for 2.25 h. It was cooled,    diluted with water, and the mixture was filtered. The crude product    was purified by preparative TLC (EtOAc) to give the title compound    (0.34 g, 24% yield) as white solid. MS: m/z 297 [M+1]⁺.-   c) 1-(3-Carboxyphenyl)quinazoline-2,4(1H,3H)-dione: The title    compound was prepared from    1-(3-methoxycarbonylphenyl)quinazoline-2,4(1H,3H)-dione and NaOH    using a procedur similar to those of compound of Example 2, and was    isolated as white solid. MS: m/z 283 [M+H]⁺.-   d)    1-(3-(4-(Pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)quinazoline-2,4(1H,3H)-dione:    The title compound was prepared from    1-(3-carboxyphenyl)quinazoline-2,4(1H,3H)-dione and    2-(piperazin-1-yl)pyrimidine using a procedure similar to those of    compound of Example 3, and was isolated as white solid. ¹H NMR    (DMSO-d₆): 11.72 (s, 1H), 8.36 (d, J=4.8 Hz, 2H), 8.02 (d, J=6.6 Hz,    1H), 7.69-7.55 (m, 5H), 7.25 (t, J=7.5 Hz, 1H), 6.65 (t, J=4.7 Hz,    1H), 6.48 (d, J=8.4 Hz, 1H), 3.80-3.20 (m, 8H). MS: m/z 429.1    [M+H]⁺.

Example 2228-Chloro-1-(3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione and8-chloro-3-(3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione

To a suspension of 8-chloroquinazoline-2,4(1H,3H)-dione (5.1 g, 25.9mmol) in toluene (50 mL) and hexamethyldisilazane (HMDS, 10.4 g, 64.9mmol) was added sulfuric acid (0.25 g, 2.6 mmol). The mixture was heatedto reflux and refluxed for 8 h until a clear solution was obtained. Thesolvent and excessive HMDS was removed via vacuum evaporation, andmethyl 3-(bromomethyl)benzoate (5.9 g, 25.9 mmol) and DMF (1 mL) wasadded to the residue. The reaction mixture was heated to 160° C. and wasstirred at this temperature for 3 h. It was diluted with 1,4-dioxane (6mL) at 100° C., and then methanol (10 mL) was added at 70° C. and it wasstirred for 30 min. The mixture was cooled to 5° C. and the precipitateswere collected. The solids was washed with methanol (10 mL) and water(20 mL), dried under vacuum for 12 h to give the title compound8-chloro-3-(3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione (2.6 g,29.1% yield) as gray solid. MS: m/z 477.1 [M+H]⁺. The filtrate wasconcentrated, and the residue was purified by preparative TLC(PE:EA=1:1) to give the other title compound8-chloro-1-(3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione (0.2 g,1.8%) as yellow solid. MS: m/z 477.1 [M+H]⁺.

Example 2238-Chloro-3-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

The compound was prepared from8-chloro-3-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione (prepared from8-chloro-3-(3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione andNaOH using a procedure similar to those of compound of Example 2), and2-(piperazin-1-yl)pyrimidine using a procedure similar to thosedescribed for the synthesis of compound of Example 3. ¹H NMR (DMSO-d₆):11.15 (s, 1H), 8.38 (d, J=4.8 Hz, 2H), 7.95 (d, J=7.8 Hz, 1H), 7.82 (d,J=7.5 Hz, 1H), 7.50-7.30 (m, 4H), 7.23 (t, J=7.8 Hz, 1H), 6.67 (t, J=4.8Hz, 1H), 5.14 (s, 2H), 3.90-3.55 (m, 8H). MS: m/z 477.1 [M+H]⁺.

Example 2248-Chloro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

The compound was prepared from8-chloro-1-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione (prepared from8-chloro-1-(3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione andNaOH using a procedure similar to those of compound of Examples 2), and2-(piperazin-1-yl)pyrimidine using a procedure similar to thosedescribed for the synthesis of compound of Example 3. ¹H NMR (DMSO-d₆):11.94 (s, 1H), 8.38 (d, J=4.8 Hz, 2H), 8.05 (d, J=6.6 Hz, 1H), 7.77 (d,J=6.6 Hz, 1H), 7.50-7.20 (m, 5H), 6.66 (t, J=4.8 Hz, 1H), 5.53 (s, 2H),3.90-3.50 (m, 8H). MS: m/z 477.1 [M+H]⁺.

Example 2258-Methyl-3-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

The compound was prepared from8-methyl-3-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione (prepared from8-methylquinazoline-2,4(1H,3H)-dione and methyl 3-(bromomethyl)benzoateusing a procedure similar to those used for Examples 222 and 223), and2-(piperazin-1-yl)pyrimidine using a procedure similar to thosedescribed for the synthesis of compound of Example 3. ¹H NMR (DMSO-d₆):10.81 (s, 1H), 8.36 (d, J=4.5 Hz, 2H), 7.83 (d, J=7.5 Hz, 1H), 7.52 (d,J=7.2 Hz, 1H), 7.45-7.30 (m, 4H), 7.13 (t, J=7.7 Hz, 1H), 6.67 (t, J=4.7Hz, 1H), 5.15 (s, 2H), 3.92-3.46 (m, 8H), 2.36 (s, 3H). MS: m/z 457.3[M+H]⁺.

Example 2268-Methyl-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

-   a) 8-Methyl-1H-benzo[d][1,3]oxazine-2,4-dione: To a solution of    2-amino-3-methylbenzoic acid (5.03 g, 33.3 mmol) in THF (50 mL) was    added triphosgene (9.92 g, 33.4 mmol). The mixture was stirred at    room temperature for 15 min and then filtered. The precipitate was    washed by THF and water, dried to give the title compound (5.10 g,    86.4% yield) as white solid. MS: m/z 178.1 [M+H]⁺.-   b) 2-Amino-N-tert-butyl-3-methylbenzamide: To a solution of    8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (3.89 g, 22.0 mmol) in    DMF (30 mL) were added DMAP (0.27 g, 2.2 mmol) and tert-butylamine    (2.55 mL, 24.1 mmol). It was stirred at room temperature overnight,    then the mixture was poured into water and the precipitate was    filtered. The solid was washed with water and dried to give the    product (1.68 g, 37.1% yield). MS: m/z 207.2 [M+H]⁺.-   c) 3-Tert-butyl-8-methylquinazoline-2,4(1H,3H)-dione: To a solution    of 2-amino-N-tert-butyl-3-methylbenzamide (0.52 g, 2.5 mmol) in THF    (20 mL) were added CDI (0.85 g, 5.2 mmol). It was refluxed    overnight, cooled to room temperature, then the mixture was poured    into water and the precipitate was filtered. The solid was washed    with water and dried to give the title compound (0.25 g, 42.6%    yield). ¹H NMR (DMSO-d₆): 10.33 (s, 1H), 7.68 (d, J=7.8 Hz, 1H),    7.41 (d, J=7.2 Hz, 1H), 7.04 (t, J=7.6 Hz, 1H), 2.31 (s, 3H), 1.66    (s, 9H).-   d)    3-Tert-butyl-8-methyl-1-(3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione:    A mixture of 3-tert-butyl-8-methylquinazoline-2,4(1H,3H)-dione (1.00    g, 4.3 mmol), methyl 3-(bromomethyl)benzoate (0.99 g, 4.3 mmol) and    MeONa (0.28 g, 5.2 mmol) in DMF (15 mL) was stirred at 50° C.    overnight. The resulting mixture was used directly for next step    reaction. MS: m/z 403.2 [M+Na]⁺.-   e) 8-Methyl-1-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione: To the    reaction mixture from above was added 6N HCl (a.q., 40 mL), and the    mixture was heated at 80° C. for 6 h. It was cooled to room    temperature, poured into water and the precipitate was filtered. The    solid was washed with water and dried to give the title compound    (0.27 g, 20.1% yield). MS: m/z 311.1 [M+H]⁺.-   f)    8-Methyl-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione:    The title compound was prepared from    8-methyl-1-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione and    2-(piperazin-1-yl)pyrimidine using a procedure similar to those    described for the synthesis of compound of Example 3. ¹H NMR    (DMSO-d₆): 11.70 (s, 1H), 8.38 (d, J=4.8 Hz, 2H), 7.92 (d, J=6.9 Hz,    1H), 7.50-7.26 (m, 5H), 7.17 (t, J=7.5 Hz, 1H), 6.65 (t, J=4.8 Hz,    1H), 5.35 (s, 2H), 3.85-3.15 (m, 8H), 2.35 (s, 3H). MS: m/z 457.2    [M+H]⁺.

Example 2278-Methoxy-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

The compound was prepared from 2-amino-3-methoxylbenzoic acid usingprocedures similar to those described for the synthesis of compound ofExample 226. ¹H NMR (DMSO-d₆): 11.76 (s, 1H), 8.38 (d, J=4.8 Hz, 2H),7.65 (d, J=6.6 Hz, 1H), 7.45-7.17 (m, 6H), 6.67 (t, J=4.7 Hz, 1H), 5.51(s, 2H), 3.80-3.64 (m, 8H), 3.56 (s, 3H). MS: m/z 473.2 [M+H]⁺.

Example 2283-(3-(4-(Pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

-   a) 3-(3-Methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione: A    suspension of quinazoline-2,4(1H,3H)-dione (2.5 g, 15.4 mmol),    methyl 3-(bromomethyl)benzoate (3.56 g, 15.4 mmol) and K₂CO₃ (4.26    g, 30.8 mmol) in DMF (30 mL) was stirred at room temperature    overnight. To the mixture was added 150 mL water and the    precipitates were collected. The crude product was purified by    chromatography on silica (CH₂Cl₂:MeOH=200:1) to give the title    compound (0.87 g, 18.2% yield) as white solid. ¹H NMR (DMSO-d₆):    11.51 (s, 1H), 8.00-7.90 (m, 2H), 7.84 (d, J=7.5 Hz, 1H), 7.75-7.55    (m, 2H), 7.47 (t, J=7.8 Hz, 1H), 7.30-7.15 (m, 2H), 5.14 (s, 2H),    3.83 (s, 3H). MS: m/z 311.2 [M+H]⁺.-   b) 3-(3-Carboxybenzyl)quinazoline-2,4(1H,3H)-dione: The title    compound was prepared from    3-(3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione using a    procedure similar to those described for the synthesis of compound    of Example 2. MS: m/z 297.2 [M+H]⁺.-   c)    3-(3-(4-(Pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione:    The title compound was prepared from    3-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione and    2-(piperazin-1-yl)pyrimidine using a procedure similar to those    described for the synthesis of compound of Example 3. ¹H NMR    (DMSO-d₆): 11.55 (s, 1H), 8.36 (d, J=4.8 Hz, 2H), 7.93 (d, J=6.9 Hz,    1H), 7.66 (t, J=7.1 Hz, 1H), 7.45-7.26 (m, 4H), 7.25-7.12 (m, 2H),    6.65 (t, J=4.7 Hz, 1H), 5.11 (s, 2H), 3.90-3.20 (m, 8H). MS: m/z    443.3 [M+H]⁺.

Example 2291-(3-(4-(Pyrimidin-2-yl)piperazine-1-carbonyl)phenethyl)quinazoline-2,4(1H,3H)-dione

The compound was prepared from1-(3-carboxyphenethyl)quinazoline-2,4(1H,3H)-dione (prepared fromquinazoline-2,4(1H,3H)-dione and methyl 3-(2-bromoethyl)benzoate using aprocedure similar to those used for Examples 1 and 2) and2-(piperazin-1-yl)pyrimidine using a procedure similar to thosedescribed for the synthesis of compound of Example 3. ¹H NMR (DMSO-d₆):11.54 (s, 1H), 8.37 (d, J=4.8 Hz, 2H), 7.78 (dd, J=7.8 and 1.5 Hz, 1H),7.73 (t, J=6.9 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.35-7.22 (m, 5H), 6.66(t, J=4.7 Hz, 1H), 4.28 (t, J=7.5 Hz, 2H), 3.80-3.20 (m, 8H), 2.95 (t,J=7.4 Hz, 1H). MS: m/z 457.4 [M+H]⁺.

Example 2308-Hydroxy-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione

A solution of BBr₃ (4N in DCM, 10 mL, 40 mmol) was added dropwise to amixture of8-methoxy-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione(60 mg, 0.13 mmol) in DCM (25 mL) at −70° C. The mixture was warmed toroom temperature and stirred at r.t overnight. After cooled at ice-bath,10 mL MeOH was added dropwise and then NH₄Cl (a.q.) was added. Themixture was extracted by DCM (50 mL×2), the combined organic layer wasdried to give crude product which was purified by TLC (DCM/MeOH=20:1) togive the target product (7.64 mg, 13.1% yield). ¹H NMR (DMSO-d₆): 11.64(s, 1H), 10.34 (s, 1H), 8.36 (d, J=4.8 Hz, 2H), 7.51 (dd, J=6.8 and 2.6Hz, 1H), 7.39-7.34 (m, 1H), 7.27-7.23 (m, 3H), 7.10-7.03 (m, 2H), 6.65(t, J=4.7 Hz, 1H), 5.63 (s, 2H), 3.85-3.53 (m, 8H). MS: m/z 459.4[M+H]⁺.

Example 231 Evaluation of the Synergistic Potentiation Effects of1-(3-(4-(Pyrimidin-2-Yl)Piperazine-1-Carbonyl)Benzyl)Quinazoline-2,4(1H,3H)-Dioneand Analogs on the Growth Inhibiting Activity of MMS Using a MTT BasedCell Viability Assay

The synergistic potentiation effect of PARP inhibitors on the growthinhibiting activity of DNA damaging anticancer drugs such as methylmethanesulphonate (MMS) were measured with SW620 human colorectal cancercells using a MTT based cell viability assay. Briefly, SW620 humancolorectal cancer cells were used to measure the cell growth inhibitingactivity of DNA alkylating anticancer drug MMS. The MMS concentrationused in the assay was carefully titrated to a level at which MMS onlyhad a minimal inhibitory effect on the cell growth, and under thisconditions it was sensitive to detect the potentiation effect of1-(arylmethyl)quinazoline-2,4(1H,3H)-diones on MMS's inhibiting activityon cell growth. SW620 cells were grown and maintained in RPMI1640(Gibco) medium supplemented with 10% FBS (Hyclone). In the first day ofexperiment, 4000 cells were seeded to each well of a 96-well cellculture plate and incubated at 37° C. and 5% CO₂ in a cell cultureincubator overnight. In the next day, the cell culture medium wasremoved. One hundred and eighty μl fresh medium containing 1.5 μg/ml MMSand 20 μl of 10-fold concentration of testing compounds or referencecompounds (AZD2281 and ABT-888) were added to each well sequencially.The serial dilutions of the reference compounds and the compounds to betested were made with a 1:3 and 1:10 fashion in DMSO. The 10-foldconcentrated solutions of these compounds were made by mixing 10 μl ofthe serial dilutions in DMSO with 90 μl fresh medium. The finalconcentration of DMSO in the medium was 1%. The cells were incubated at37° C. in 5% CO₂ cell culture incubator for additional 5 days (120hours). Afterwards, the 96-well cell culture plate was taken out and 20μl of MTT solution was added to each well and incubated at 37° C. for 4h. The medium was removed and 100 μl DMSO was added to each well. The96-well cell culture plates were shaked adequately for 10 min and readedin a Varioskan Flash plate reader (Thermo Fisher Scientific) at 520 and690 nm. The data were analyzed by Prism 5 software (GraphPad). Theobtained 520 nm absorbance readings substracting corresponding 690 nmreading were analyzed and plotted against the Log scale of the compoundconcentrations. The curves were fitted using the following equation tocalculate the IC₅₀ value of each compound, Y (absorbance)=minimalabsorbance value+(maximal absorbance value−minimal absorbancevalue)/(1+10̂(Log C−Log IC₅₀)), C was the compound concentration.

The calculated IC₅₀ values are listed in Table 1. These values reflectthe potentiation effect of 1-(arylmethyl)quinazoline-2,4(1H,3H)-dioneson the growth inhibiting activity of a fixed concentration of MMS in aMTT based cell viability assays.

TABLE 1 Substituted 1-(arylmethyl)quinazoline-2,4(1H,3H)-dionespotentiate the growth inhibiting activity of MMS (IC₅₀) Example # 1 2 34 5 6 7 8 IC₅₀ (nM) >10000 >10000 90 12 5356 7026 5269 112 Example # 910 11 12 13 14 15 16 IC₅₀ (nM) 500 439 618 533 727 102 666 7259 Example# 17 18 19 20 21 22 23 24 IC₅₀ (nM) >10000 >10000 >10000391 >10000 >10000 8.2 26 Example # 25 26 27 28 29 30 31 32 IC₅₀ (nM) 9.8149 83 >10000 >10000 119 2595 106 Example # 33 34 35 36 37 38 39 40 IC₅₀(nM) 130 294 265 >10000 >10000 >10000 604 182 Example # 41 42 43 44 4546 47 48 IC₅₀ (nM) 11 78 51 6.8 34 21 54 56 Example # 49 50 51 52 53 5455 56 IC₅₀ (nM) 32 37 33 55 59 217 89 30 Example # 57 58 59 60 61 62 6364 IC₅₀ (nM) 46 171 >10000 >10000 61 816 50 177 Example # 65 66 67 68 6970 71 72 IC₅₀ (nM) 417 991 2054 673 352 136 70 80 Example # 73 74 75 7677 78 79 80 IC₅₀ (nM) 3379 >10000 2661 ND 2964 269 5543 >10000 Example #81 82 83 84 85 86 87 88 IC₅₀ (nM) 99 459 72 52 25 86 35 137 Example # 8990 91 92 93 94 95 96 IC₅₀ (nM)ND >10000 >10000 >10000 >10000 >10000 >10000 >10000 Example # 97 98 99100 101 102 103 104 IC₅₀ (nM) >10000 >10000 >10000 202 117 87 45 8.3Example # 105 106 107 108 109 110 111 112 IC₅₀ (nM) 7.9 105 6.3 78 48 7227 14 Example # 113 114 115 116 117 118 119 120 IC₅₀ (nM) 9.6 51 19 485.1 0.82 0.72 42 Example # 121 122 123 124 125 126 127 128 IC₅₀ (nM) 4.5Td 15 9.9 6.7 18 13 37 Example # 129 130 131 132 133 134 135 136 IC₅₀(nM) 18 15 17 4.1 4.1 5.8 6.8 7.1 Example # 137 138 139 140 141 142 143144 IC₅₀ (nM) 7.0 351 16 37 12 22 15 2.8 Example # 145 146 147 148 149150 151 152 IC₅₀ (nM) 12 3.4 2.7 2.1 14 25 18 13 Example # 153 154 155156 157 158 159 160 IC₅₀ (nM) 9.2 7.3 23 28 18 7.8 648 394 Example # 161162 163 164 165 166 167 168 IC₅₀ (nM) 506 1193 28 6.2 49 4.0 5.2 15Example # 169 170 171 172 173 174 175 176 IC₅₀ (nM) 3.4 120 70 9.5 22894 16 15 Example # 177 178 179 180 181 182 183 184 IC₅₀ (nM) >10000 7.912 3.1 4.9 16 13 62 Example # 185 186 187 188 189 190 191 192 IC₅₀ (nM)6.7 24 27 7.8 10 21 192 7.2 Example # 193 194 195 196 197 198 199 200IC₅₀ (nM) 4.5 18 1440 985 >10000 >10000 19 >10000 Example # 201 202 203204 205 206 207 208 IC₅₀(nM) >10000 >10000 >10000 >10000 >10000 >10000 >10000 37 Example # 209210 211 212 213 214 215 216 IC₅₀ (nM) 103 10 145 19 58 517 1388 >10000Example # 217 218 219 220 221 223 224 225 IC₅₀ (nM) 2.5 103481 >10000 >10000 >10000 1113 >10000 Example # 226 227 228 229 230AZD2281 ABT-888 IC₅₀ (nM) 84 13 >10000 >10000 2.6 28 2642 ND, notdetermined.

In summary,1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione(Example 4) and analogs have excellent potentiation effects on thegrowth inhibiting activity of DNA damaging anticancer agent MMS in a MTTbased cell viability assay.

Example 232 Determination of the Synergistic Potentiation Effect of1-(3-(4-(Pyrimidin-2-Yl)Piperazine-1-Carbonyl)Benzyl)Quinazoline-2,4(1H,3H)-Dioneand Analogs on MMS Induced Apoptosis Using a Cell Based Caspase-3Activity Assay

Human breast cancer cell line T47D was used to determine thepotentiation effect of PARP inhibitors on the apoptosis inducingactivity of DNA damaging anticancer drugs such as MIMS. Intracellularcaspase-3 activity was used to measure cell apoptosis. The dose responseeffect of MMS to induce intracellular caspase activity was carefullytitrated and the concentration that only induces a minimal level ofcaspase activity was used to test the potentiation effect of PARPinhibitors. Briefly, T47D cells were grown in DMEM/F12 cell culturemedium (Hyclone) supplemented with 0.2 U/ml insulin (Genview) and 10%FBS (Hyclone). A day before experiment, 20000 of T47D cells were seededto each well of a 96-well cell culture plate and maintained at 37° C.and 5% CO₂ in a cell culture incubator overnight. On the day ofexperiment, cell culture medium was removed. One hundred and eighty μlof fresh medium containing 100 nM MMS was added to each well andfollowed by 20 μl medium containing 10 folds of the concentrations ofexperimental drugs or reference compounds (ADZ2281 and ABT-888). Theserial dilutions of the compounds to be tested and the referencecompounds were made in a 1:3 and 1:10 fashion in DMSO. The 10-foldcompound solutions were made by mixing 10 μl DMSO serial dilutionsolutions with 90 μl fresh growth medium. Twenty four hours later, thecells in the 96-well plates were centrifuged at 1000 g for 5 min and thesupernatants were removed. Fifty μl lysis buffer (10 mM Tris, pH7.5,0.1M NaCl, 1 mM EDTA, 0.01% Triton X-100) was added to each well and theplates were shaked horizontally for 30 min at 4° C. After centrifugationat 1000 g at 4° C. for 10 min, 20 μl of supernatant was transferred fromeach well to a corresponding well in a 384-well black plate. Twenty μlof buffer (20 mM PIPES, pH7.4, 4 mM EDTA and 0.2% CHAPS) containing 20μM fluorescent caspase-3 substrate ((Ac-DEVD)₂-R110, AnaSpec Cat#60304-5) was added to each well afterwards. The plates were shaked touniformly mix the wells and incubated at 37° C. for 3 h. Thefluorescence intensity was measured using the following wavelength: ex:496 nm, em: 520 nm using a fluorescence plate reader (Varioskan Flash,Thermo Fisher Scientific). The caspase-3 activity induced by thecompounds was expressed as a relativefluorescence unit (RFU). Theobtained fluorescence readings were analyzed using a commercial graphicsoftware (GraphPad Prism 5) and plotted against the Log value of thecompound concentrations. The EC₅₀ values were obtained by fitting thedata points with the equation of Y (fluorescence reading)=minimalfluorescence reading+(maximal fluorescence reading−minimal fluorescencereading)/(1+10̂(Log EC50−Log C)), where C is the concentration of thetesting compound.

The synergistic potentiation effect of compounds on MMS inducedapoptosis in T47D cells is expressed as EC₅₀ values and listed in Table2.

TABLE 2 Substituted 1-(arylmethyl)quinazoline-2,4(1H,3H)-dionespotentiate the apoptosis inducing activity of MMS (EC₅₀) Example # 1 2 34 5 6 7 8 EC₅₀ (nM) >10000 >10000 56 12 450 2518 2655 120 Example # 9 1011 12 13 14 15 16 EC₅₀ (nM) 426 400 214 318 6601 39 803 9206 Example #17 18 19 20 21 22 23 24 EC₅₀ (nM) 5018 >10000 >10000 139 5797 >10000 4.020 Example # 25 26 27 28 29 30 31 32 EC₅₀ (nM) 3.9 20 51 5894 >10000 39112 96 Example # 33 34 35 36 37 38 39 40 EC₅₀ (nM) 96 104 238 >100001914 267 614 29 Example # 41 42 43 44 45 46 47 48 EC₅₀ (nM) 2.2 11 185.7 11 6.6 2.6 8.2 Example # 49 50 51 52 53 54 55 56 EC₅₀ (nM) 10 13 2022 18 124 20 16 Example # 57 58 59 60 61 62 63 64 EC₅₀ (nM) 22108 >10000 >10000 17 379 15 51 Example # 65 66 67 68 69 70 71 72 EC₅₀(nM) 373 604 4820 635 76 34 67 41 Example # 73 74 75 76 77 78 79 80 EC₅₀(nM) 811 2111 2869 ND 5206 112 3219 1192 Example # 81 82 83 84 85 86 8788 EC₅₀ (nM) 63 154 21 18 7.6 27 27 67 Example # 89 90 91 92 93 94 95 96EC₅₀ (nM) ND 4168 1987 2926 >10000 >10000 >10000 >10000 Example # 97 9899 100 101 102 103 104 EC₅₀ (nM) >10000 >10000 >10000 70 20 26 29 2.6Example # 105 106 107 108 109 110 111 112 EC₅₀ (nM) 14 217 9.5 68 23 321.7 2.9 Example # 113 114 115 116 117 118 119 120 EC₅₀ (nM) 17 19 23 135.8 3.1 3.0 8.8 Example # 121 122 123 124 125 126 127 128 EC₅₀ (nM) 4.98.4 11 3.8 22 6.5 4.1 12 Example # 129 130 131 132 133 134 135 136 EC₅₀(nM) 49 87 20 0.93 2.1 4.7 9.8 3.2 Example # 137 138 139 140 141 142 143144 EC₅₀ (nM) 2.1 281 4.0 8.9 13 3.8 6.0 3.4 Example # 145 146 147 148149 150 151 152 EC₅₀ (nM) 6.5 4.1 3.4 2.3 5.8 16 5.2 5.1 Example # 153154 155 156 157 158 159 160 EC₅₀ (nM) 2.0 6.7 12 14 26 8.6 220 261Example # 161 162 163 164 165 166 167 168 EC₅₀ (nM) 405 495 42 2.1 181.6 5.0 3.8 Example # 169 170 171 172 173 174 175 176 EC₅₀ (nM) 1.0 4323 3.2 122 37 14 10 Example # 177 178 179 180 181 182 183 184 EC₅₀ (nM)743 11 7.4 1.4 2.4 14 6.1 18 Example # 185 186 187 188 189 190 191 192EC₅₀ (nM) 2.1 6.8 30 ND ND ND ND 3.1 Example # 193 194 195 196 197 198199 200 EC₅₀ (nM) 1.6 11 471 >10000 >10000 >10000 4.9 >10000 Example #201 202 203 204 205 206 207 208 EC₅₀(nM) >10000 >10000 >10000 >10000 >10000 >10000 >10000 24 Example # 209210 211 212 213 214 215 216 EC₅₀ (nM) 294 15 166 45 590 654 743 >10000Example # 217 218 219 220 221 223 224 225 EC₅₀ (nM) 19 37445 >10000 >10000 >10000 274 >10000 Example # 226 227 228 229 230AZD2281 ABT-888 EC₅₀ (nM) 24 40 >10000 >10000 3.2 24 3494 ND, notdetermined.

In summary, as measured by the intracellular caspase activity,1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione(Example 4) and its analogs have shown excellent potentiation effect onDNA damaging anticancer drug MMS induced cancer cell apoptosis.

Example 233 Determination of the Cell Growth Inhibiting Activity of1-(3-(4-(Pyrimidin-2-Yl)Piperazine-1-Carbonyl)Benzyl)Quinazoline-2,4(1H,3H)-Dioneand Analogs on BRCA-2 Deficient CAPAN-1 Pancreatic Duck Cancer CellsUsing a MTT Based Cell Viability Assay

BRCA-deficient cancer cells are sensitive to PARP inhibition. In thepresence of PARP inhibitors, BRCA-deficient cancer cells could not growand eventually will lead to death of cells. BRCA-2 deficient CAPAN-1human pancreatic cancer cells were used to test the growth inhibitingactivity of substituted 1-(arylmethyl)quinazoline-2,4(1H,3H)-diones.Briefly, CAPAN-1 cells are grown and maintained in IMEM mediumsupplemented with 20% FBS. The assay takes 10 days to finish. On day 1,6000 CAPAN-1 cells are seeded to each well of a 96-well plate. The cellsare incubated at 37° C. in a cell culture incubator overnight. In thenext day, serial dilutions of compounds to be tested and referencecompound (AZD2281) were prepared with a 1:3 and 1:10 fashion in DMSO.Ten-fold compound solutions were made by mixing 10 DMSO serial dilutionsolutions with 90 μl fresh growth medium. The cell culture medium wasremoved and 180 μl fresh media with FBS and 20 μl of compound solutionswere added to each well. The final concentration of DMSO was 1%. Cellswere then returned to the CO₂ cell culture incubator and incubated at37° C. for two days (day 3 and day 4). On day 5, the same procedure aswhat was done on day 2 was repeated. Cell culture medium was removed andfresh medium containing serial dilutions of compounds or referencecompounds were added. Cells were returned to the CO₂ cell cultureincubator and incubated for two more days. On day 8, same procedure wasrepeated again and fresh medium containing the testing compounds orreference compounds were added and incubated for an additional 2 days.On day 10, 20 μl of MTT reagent (5 mg/ml) was added to each well of thecell culture plate and incubated for 4 h. The cell culture media wasremoved and 100 μl DMSO was added to each well. The 96-well cell cultureplates were shaked horizontally for 10 min and readed in a VarioskanFlash plate reader (Thermo Fisher Scientific) at 520 and 690 nm. Theobtained 520 nm absorbance readings substracting corresponding 690 nmreading were analyzed using a commercial graphic software (GraphPadPrism 5) and plotted against the Log scale of the compoundconcentrations. The curves were fitted using the following equation tocalculate the IC₅₀ value of each compound, Y (520 nm-690 nm)=minimalabsorbance value+(maximal absorbance value−minimal absorbancevalue)/(1+10̂(Log C−Log IC₅₀)), where C was the concentration of testingcompounds.

The inhibitory effect of compounds on the CAPAN-1 cell growth isexpressed as IC₅₀ values and listed in Table 3.

TABLE 3 Growth inhibition of CAPAN-1 cells by selected substituted1-(arylmethyl)quinazoline-2,4(1H,3H)-diones (IC₅₀) Ex- 3 4 8 11 15 20 2324 ample # IC₅₀ 445 55 2360 1841 >10000 4942 160 735 (nM) Ex- 25 26 2730 40 41 42 43 ample # IC₅₀ 98 400 281 1785 1739 208 2539 974 (nM) Ex-44 45 46 48 49 50 51 56 ample # IC₅₀ 318 668 446 168 421 173 402 1181(nM) Ex- 65 69 70 81 83 85 100 101 ample # IC₅₀ 3189 1982 339 421 746291 312 1049 (nM) Ex- 103 104 105 107 111 112 113 117 ample # IC₅₀ 665452 97 161 77 767 170 39 (nM) Ex- 118 119 123 124 127 128 132 133 ample# IC₅₀ 54 56 111 137 44 442 17 22 (nM) Ex- 134 136 139 140 142 143 144145 ample # IC₅₀ 45 40 36 155 223 73 78 146 (nM) Ex- 147 149 150 152 154155 157 161 ample # IC₅₀ 47 52 176 121 56 142 202 3547 (nM) Ex- 168 172176 185 186 188 189 190 ample # IC₅₀ 1465 389 187 358 167 472 736 1383(nM) Ex- 199 210 212 217 AZD2281 ample # IC₅₀ 25 948 3445 >10000 460(nM)

In summary,1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione(Example 4) and analogs are excellent inhibitors of CAPAN-1 cell growth,suggesting that they are good PARP inhibitors.

Example 234 Measurement of the Inhibitory Effect of1-(3-(4-(Pyrimidin-2-Yl)Piperazine-1-Carbonyl)Benzyl)Quinazoline-2,4(1H,3H)-Dioneand Analogs on PARP-1 Enzymtic Activity

The measurement of PARP-1 enzymtic activity was achieved by using acommercial 96-well colorimetric assay kit (4676-096-K, Trevigen, Inc.Gaithersburg, Md. 20877 USA). Briefly, PARP-1 catalyzes theNAD-dependent addition of poly(ADP-ribose) to its nuclear proteinsubstrates such as histones. The assay kit measures the incorporation ofbiotynylated poly(ADP-ribose) onto histone proteins in a 96-well format.

Reference compound (AZD2281) and compounds to be tested are seriallydiluted 1:10 with a 1× buffer. To each well of histone pre-coated plate10 μl of 5-fold concentrations of testing compounds or referencecompound, 15 μl of PARP-1 enzyme (0.5 unit) and 25 μl reaction bufferwere added and the plates were incubated at room temperature for 60 min.The plates were washed with 200 μl PBS with 0.1% Triton X-100 twice andthen with 200 μl PBS twice. The residual liquid was removed by carefullytapping the plates on paper towels. Equal volumes of PeroxyGlow™solution A and B were mixed and 100 μl of the solution was added to eachwell. The luminescence readings were read immediately in a VarioskanFlash plate reader (Thermo Fisher Scientific). The obtained luminescencereadings were analyzed using a commercial graphic software (GraphPadPrism 5) and plotted against the Log scale of the compoundconcentrations. The IC₅₀ values were obtained by fitting the data pointswith the equation of Y (Luminescence reading)=minimal luminescencereading+(maximal luminescence reading−minimal luminescencereading)/(1+10̂(Log C−Log EC₅₀)), where C is the concentration of thetesting compound.

The inhibitory effect of compounds on the PARP-1 enzymatic activity isexpressed as IC₅₀ values and listed in Table 4.

TABLE 4 The inhibitory effect of substituted1-(arylmethyl)quinazoline-2,4(1H,3H)-diones on PARP-1 enzymatic activity(IC₅₀) Example # 3 4 8 14 25 44 127 132 135 139 IC₅₀ (nM) 4.2 0.96 5.32.3 0.21 0.88 0.37 1.19 1.74 1.3 Example # 144 147 189 AZD2281 IC₅₀ (nM)1.15 1.2 2.20 2.2

In summary, as measured in the PARP-1 enzymatic assay,1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione(Example 4) and analogs are potent PARP-1 inhibitors.

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the invention or anyembodiment thereof. All patents, patent applications and publicationscited herein are fully incorporated by reference herein in theirentirety.

1. A compound having the Formula I:

or a pharmaceutically acceptable salt or prodrug thereof, wherein: Ar isan aryl or heteroaryl, substituted with a substituted carbonyl or methylat the meta-position; and R₁-R₆ independently are hydrogen, halo,optionally substituted amino, optionally substituted alkoxy, optionallySubstituted C₁₋₁₀ alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,aminoalkyl, carboxyalkyl, ethylenedioxo, nitro, cyano, acylamido,hydroxy, thiol, acyloxy, azido, carboxy, carbonylamido or optionallysubstituted alkylthiol.
 2. The compound of claim 1, wherein R₅ and R₆ ishydrogen, Ar is phenyl, pyridyl or furanyl, substituted with asubstituted carbonyl at the meta-position.
 3. The compound of claim 1,wherein said compound has Formula II:

or pharmaceutically acceptable salts or prodrugs thereof, wherein: R₁-R₄independently are hydrogen, halo, optionally substituted amino,optionally substituted alkoxy, optionally substituted C₁₋₁₀ alkyl,haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, carboxyalkyl,nitro, ethylenedioxo, cyano, acylamido, hydroxy, thiol, acyloxy, azido,carboxy, carbonylamido or optionally substituted alkylthiol, R₇-R₁₀independently are hydrogen, halo, optionally substituted amino, alkoxy,C₁₋₁₀ alkyl, haloalkyl, aryl, heteroaryl, a carbocyclic group, aheterocyclic group, alkenyl, alkynyl, arylalkyl, arylalkenyl,arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl,carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, hydroxyalkoxy,aminoalkyl, aminoalkoxy, carboxyalkyl, carboxyalkoxy, nitro, cyano,acylamido, aminocarbonyl, hydroxy, thiol, acyloxy, azido, carboxy,carbonylamido, alkylsulfonyl, aminosulfonyl, dialkylaminosulfonyl,alkylsulfinyl, alkylthiol, or substituted carbonyl, and R₁₁ is anoptionally substituted amino, hydrazino, alkoxy, C₁₋₁₀ alkyl, haloalkyl,aryl, heteroaryl, carbocyclic group, heterocyclic group, alkenyl,alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl,heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl,hydroxyalkyl, hydroxyalkoxy, aminoalkyl, aminoalkoxy, carboxyalkyl,carboxyalkoxy, acylamido, hydroxy, thiol, acyloxy, carbonylamido, oralkylthiol.
 4. The compound of claim 1, wherein said compound hasFormula III:

or pharmaceutically acceptable salts or prodrugs thereof, wherein: R₁-R₄independently are hydrogen, halo, optionally substituted amino,optionally substituted alkoxy, optionally substituted C₁₋₁₀ alkyl,haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, carboxyalkyl,nitro, cyano, ethylenedioxo, acylamido, hydroxy, thiol, acyloxy, azido,carboxy, carbonylamido or optionally substituted alkylthiol; R₇₋₁₀independently are hydrogen, halo, optionally substituted amino, alkoxy,C₁₋₁₀ alkyl, haloalkyl, aryl, carbocyclic, a heterocyclic group, aheteroaryl group, alkenyl, alkenyl, arylalkyl, arylalkenyl, arylalkynyl,heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl,heterocycloalkyl, hydroxyalkyl, hydroxyalkoxy, aminoalkyl, aminoalkoxy,carboxyalkyl, carboxyalkoxy, nitro, cyano, acylamido, aminocarbonyl,hydroxy, thiol, acyloxy, azido, carboxy, carbonylamido, alkylsulfonyl,aminosulfonyl, dialkylaminosulfonyl, alkylsulfinyl, alkylthiol, orsubstituted carbonyl; and R₁₂ is an optionally substituted C₁₋₁₀ alkyl,haloalkyl, cycloalkyl, aryl, heteroaryl, carbocyclic group, heterocyclicgroup alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl,heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl,heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkylcarbonyl,acyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,heterocyclocarbonyl, aminocarbonyl, alkylsulfonyl, cycloalkylsulfonyl,or aminosulfonyl.
 5. The compound of claim 4, wherein R₁ or R₂ ishydrogen, fluoro, chloro, bromo or methyl; R₄ is hydrogen, fluoro,methyl, methoxy or hydroxy; R₇, R₈, R₉, or R₁₀ is hydrogen or fluoro. 6.The compound of claim 4, wherein R₁₂ cycloalkyl, aryl, heteroaryl,carbocyclic group, heterocyclic group, arylalkyl, heteroarylalkyl,carbocycloalkyl, heterocycloalkyl, alkylcarbonyl, cycloalkylcarbonyl,arylcarbonyl, heteroarylcarbonyl or heterocyclocarbonyl.
 7. The compoundof claim 1, wherein said compound is selected from the group consistingof: 1-(3-Methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione;1-(3-Carboxybenzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-Cyclohexylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-([1,2,4]Triazolo[4,3-b]pyridazin-6-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-Ethylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-di one;1-(3-(4-Benzoylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(4-Fluorobenzoyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(4-Chlorobenzoyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(4-Bromobenzoyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(4-Methoxybenzoyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Tetrahydro-2H-pyran-4-yl)carbonylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclopropylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Ethylsulfonyl)piperazine-1-catbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-Acetylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-Phenylpiperidine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-Phenylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Pyrazin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(4-Fluoro-3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione;1-(3-Carboxy-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;1-(4-Fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(4-Fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Benzo[d]isothiazol-3-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Piperidin-1-yl)piperidine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Pyridin-4-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclobutylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Furan-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Furan-3-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Thiophene-3-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Pyridine-3-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Pyridine-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Pyridine-4-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-Phenoxypiperidine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclopropylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;1-(4-Fluoro-3-(4-(pyrazin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Benzo[d]isothiazol-3-yl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclobutylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-Benzoylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;1-(4-Fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(4-Fluoro-3-(4-(furan-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;1-(6-Fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(6-Fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(6-Fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclobutylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;1-(6-Fluoro-3-(4-(furan-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(6-Chloro-3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(6-Chloro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(6-Chloro-3-(4-(cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(6-Chloro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(2-Chloro-3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(2-Chloro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(2-Fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)-2-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;1-(5-Fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)-5-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;1-(4-Chloro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(4-Chloro-3-(4-(cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-((2-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)furan-5-yl)methyl)quinazoline-2,4(1H,3H)-dione;1-((2-(4-(Benzo[d]isothiazol-3-yl)piperazine-1-carbonyl)furan-5-yl)methyl)quinazoline-2,4(1H,3H)-dione;1-((2-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)pyridin-6-yl)methyl)quinazoline-2,4(1H,3H)-dione;1-((2-(4-(Pyridin-2-yl)piperazine-1-carbonyl)pyridin-6-yl)methyl)quinazoline-2,4(1H,3H)-dione;1-((2-(4-(Pyrimidin-2-yl)piperazine-1-carbonyl)pyridin-6-yl)methyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Thiazol-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclohexylmethyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclopentylmethyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclohexylsulfonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)-7-fluoroquinazoline-2,4(1H,3H)-dione;7-Fluoro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)-7-methylquinazoline-2,4(1H,3H)-dione;7-Methyl-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;6-Methyl-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)-6-methylquinazoline-2,4(1H,3H)-dione;1-(4-Fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-6-methylquinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-6-methylquinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-6-methylquinazoline-2,4(1H,3H)-dione;6-Bromo-1-(3-(4-(cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;6-Bromo-1-(3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;6-Bromo-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)-6-nitroquinazoline-2,4(1H,3H)-dione;6-Nitro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)-6-nitroquinazoline-2,4(1H,3H)-dione;5-Chloro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;5-Chloro-1-(3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;5-Chloro-1-(3-(4-(cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;5-Chloro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;5-Chloro-1-(3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;5-Chloro-1-(3-(4-(cyclohexylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;5-Chloro-1-(4-fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;5-Chloro-1-(4-fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;5-Chloro-1-(3-(4-(cyclohexylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;5-Chloro-1-(3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;5-Chloro-1-(6-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;6-Chloro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;6-Chloro-1-(3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;6-Chloro-1-(3-(4-(cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;6-Chloro-1-(3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;6-Chloro-1-(3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;6-Chloro-1-(3-(4-(cyclobutylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;6-Chloro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;6-Chloro-1-(3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;6-Chloro-1-(3-(4-(cyclohexylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;6-Chloro-1-(4-fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;6-Chloro-1-(4-fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;6-Chloro-1-(3-(4-(cyclopropylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline)-2,4(1H,3H)-dione;6-Chloro-1-(6-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;6-Chloro-1-(3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;6-Chloro-1-(3-(4-(cyclohexylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;6-Chloro-1-(6-fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;5-Fluoro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;5-Fluoro-1-(3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;5-Fluoro-(1-(3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline)-2,4(1H,3H)-dione;5-Fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;5-Fluoro-1-(4-fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;5-Fluoro-1-(4-fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-Benzoylpiperazine-1-carbonyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)-8-fluoroquinazoline-2,4(1H,3H)-dione;6-Fluoro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;6-Fluoro-1-(3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;6-Fluoro-1-(3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)benzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione;6-Fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;6-Fluoro-1-(4-fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;6-Fluoro-1-(4-fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione;6-Fluoro-1-(6-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;6-Fluoro-1-(6-fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;6-Fluoro-1-(6-fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione;5-Fluoro-1-(6-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;5-Fluoro-1-(6-fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;5-Fluoro-1-(6-fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclohexylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;5-Methyl-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)-5-methylquinazoline-2,4(1H,3H)-dione;7-Chloro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;7-Chloro-1-(3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclopropylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-5-fluoroquinazoline)-2,4(1H,3H)-dione;6-Chloro-(1-(3-(4-benzoylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline)-2,4(1H,3H)-dione;1-(3-(4-(Cyclobutylcarbonyl)piperazine-1-carbonyl)benzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclobutylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;6-Chloro-1-(3-(4-(cyclobutylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;5-Chloro-1-(3-(4-(cyclobutylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;6-Chloro-1-(3-(4-(cyclobutylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;5-Chloro-1-(3-(4-(cyclobutylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)quinazoline-2,4(1H,3H)-dione;5-Chloro-1-(6-fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;5-Fluoro-1-(4-fluoro-3-(4-(furan-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;5-Chloro-1-(6-fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;6-Chloro-1-(6-fluoro-3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;6-Chloro-1-(5-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;5-Fluoro-1-(5-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-Cyclopentylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclopropylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclobutylcarbonyl)piperazine-1-carbonyl)benzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclobutylcarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione;1-(3-(4-Benzoylpiperazine-1-carbonyl)-4-fluorobenzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclobutylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclobutylcarbonyl)piperazine-1-carbonyl)-6-fluorobenzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione;5-Fluoro-1-(6-fluoro-3-(4-(furan-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;6-Fluoro-1-(4-fluoro-3-(4-(furan-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;6-Fluoro-1-(5-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(6-Chloro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-6-fluoroquinazoline-2,4(1H,3H)-dione;6-Fluoro-1-(4-fluoro-3-(4-(thiazol-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;5-Fluoro-1-(4-fluoro-3-(4-(thiazol-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(4-Fluoro-3-(4-(thiazol-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclohexylcarbamoyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(4-Fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dionehydrochloride; 5-Fluoro1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dionehydrochloride;1-(3-(4-(Pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dionehydrochloride;1-(3-([1,2,4]Triazolo[4,3-a]pyridine-6-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;6-Fluoro-1-((2-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)pyridin-6-yl)methyl)quinazoline-2,4(1H,3H)-dione;5-Fluoro-1-(4-fluoro-3-(4-methoxybenzylcarbamoyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(3-Chlorobenzylcarbamoyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;1-(3-(Benzylcarbamoyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;5-Methoxy-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;6-Methoxy-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(5-Bromopyrimidin-2-aminocarbamoyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;1-(3-(4-(Pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione;6,7-Ethylenedioxo-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;5-Fluoro-1-(6-methoxy-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H))-dione;7-Methoxy-1-(3-(4(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;5-Fluoro-1-(4-fluoro-3-(44(tetrahydrofuran-2-carbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H-dione;5-Fluoro-1-(4-nitro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclohexylpiperazine-1-carbonyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;5-Fluoro-1-(4-fluoro-3-(4-phenylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;5-Fluoro-1-(4-fluoro-3-(4-phenylpiperidine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(4-Bromo-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;6,7-Methylenedioxo-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;1-(3-(4-(Cyclohexylmethyl)piperazine-1-carbonyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H)-dione;8-Fluoro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;6-Amino-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;8-Chloro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;8-Methyl-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;8-Methoxy-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;8-Hydroxy-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione;or a pharmaceutically acceptable salt or prodrug thereof.
 8. A method oftreating or preventing a disorder responsive to the inhibition of PARPactivity in a mammal suffering therefrom, comprising administering tothe mammal in need of such treatment a therapeutically effective amountof a compound of claim
 1. 9. The method of claim 8, wherein saiddisorder is cancer.
 10. The method according to claim 9, wherein saidcancer is liver cancer, melanoma, Hodgkin's disease, non-Hodgkin'slymphomas, acute or chronic lymphocytic leukemia, multiple myeloma,neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma,Wilms' tumor, cervical carcinoma, testicular carcinoma, soft-tissuesarcoma, chronic lymphocytic leukemia, primary macroglobulinemia,bladder carcinoma, chronic granulocytic leukemia, primary braincarcinoma, malignant melanoma, small-cell lung carcinoma, stomachcarcinoma, colon carcinoma, malignant pancreatic insulinoma, malignantcarcinoid carcinoma, malignant melanoma, choriocarcinoma, mycosisfungoide, head or neck carcinoma, osteogenic sarcoma, pancreaticcarcinoma, acute granulocytic leukemia, hairy cell leukemia,neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, genitourinarycarcinoma, thyroid carcinoma, esophageal carcinoma, malignanthypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrialcarcinoma, polycythemia vera, essential thrombocytosis, adrenal cortexcarcinoma, skin cancer, or prostatic carcinoma.
 11. The method of claim10, further comprising administering at least one known anticanceragent, or a pharmaceutically acceptable salt of said agent.
 12. Themethod according to claim 10, wherein said compound is administeredtogether with at least one compound selected from the group consistingof busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide,temozolomide, bendamustine, cis-platin, mitomycin C, bleomycin,carboplatin, camptothecin, irinotecan, topotecan, doxorubicin,epirubicin, aclarubicin, mitoxantrone, elliptinium, etoposide,5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate,5-fluoro-2′-deoxy-uridine, fludarabine, nelarabine, ara-C, alanosine,pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine,vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone,cabazitaxel, docetaxel, campath, Panitumumab, Ofatumumab, Avastin,Herceptin®, Rituxan®, imatinib, gefitinib, erlotinib, lapatinib,sorafenib, sunitinib, nilotinib, dasatinib, pazopanib, temsirolimus,everolimus, vorinostat, romidepsin, tamoxifen, letrozole, fulvestrant,mitoguazone, octreotide, retinoic acid, arsenic trioxide, zoledronicacid, bortezomib, thalidomide or lenalidomide.
 13. The method of claim10, further comprising treating said mammal with radiation-therapy. 14.A pharmaceutical composition comprising the compound of claim 1 and apharmaceutically acceptable carrier.
 15. The pharmaceutical compositionof claim 14, further comprising at least one known anticancer agent, ora pharmaceutically acceptable salt of said agent.
 16. The pharmaceuticalcomposition of claim 14, further comprising at least one compoundselected from the group consisting of busulfan, melphalan, chlorambucil,cyclophosphamide, ifosfamide, temozolomide, bendamustine, cis-platin,mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan,topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone,elliptinium, etoposide, 5-azacytidine, gemcitabine, 5-fluorouracil,methotrexate, 5-fluoro-2′-deoxy-uridine, fludarabine, nelarabine, ara-C,alanosine, pralatrexate, pemetrexed, hydroxyurea, thioguanine,colchicine, vinblastine, vincristine, vinorelbine, paclitaxel,ixabepilone, cabazitaxel, docetaxel, campath, Panitumumab, Ofatumumab,Avastin, Herceptin®, Rituxan®, imatinib, gefitinib, erlotinib,lapatinib, sorafenib, sunitinib, nilotinib, dasatinib, pazopanib,temsirolimus, everolimus, vorinostat, romidepsin, tamoxifen, letrozole,fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic trioxide,zoledronic acid, bortezomib, thalidomide or lenalidomide.
 17. (canceled)18. The compound of claim 4, wherein R₁ and R₂ each independently areselected from the group consisting of H, halo, C₁-C₆ alkyl or C₁-C₆alkoxy; R₃ is H; R₄ is selected from the group consisting of H, halo,C₁-C₆ alkyl, C₁-C₆ alkoxy or hydroxyl; R₇, R₈, R₉ and R₁₀ are eachindependently selected from the group consisting of H and halo; and R₁₂is optionally substituted cycloalkyl, aryl, heteroaryl, carbocyclicgroup, heterocyclic group, arylalkyl, heteroarylalkyl, carbocycloalkyl,heterocycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl,heteroarylcarbonyl or heterocyclocarbonyl.
 19. The compound of claim 18,wherein R₁₂ is optionally substituted C₃₋₈ cycloalkylcarbonyl, pyridyl,pyrimidinyl, benzoyl, phenyl, piperidinyl, thienylcarbonyl,furylcarbonyl, pyrazinyl, or thiazolyl.
 20. The compound of claim 4,wherein R₁ and R₂ each independently are selected from the groupconsisting of hydrogen, fluoro, chloro, bromo or methyl; R₃ is H; R₄ isselected from the group consisting of hydrogen, fluoro, methyl, methoxyor hydroxy; R₇, R₈, R₉ and R₁₀ are each independently selected from thegroup consisting of H and fluoro; and R₁₂ is C₃₋₈ cycloalkylcarbonyl,pyridyl, pyrimidinyl, benzoyl, phenyl, piperidinyl, thienylcarbonyl,furylcarbonyl, pyrazinyl, or thiazolyl, optionally substituted by 1, 2,3, or 4 substituents selected from the group consisting of halo, C₁-C₆haloalkyl, C₁-C₆ alkyl, amino, hydroxy, or C₁-C₆ alkoxy.
 21. The methodof claim 8, comprising administering to the mammal in need of suchtreatment a therapeutically effective amount of a compound of claim 4.